Substituted hydroxamic acids and uses thereof

ABSTRACT

This invention provides compounds of formula (I): 
     
       
         
         
             
             
         
       
         
         
           
             wherein R 1 , R 2 , G, n, p and q have values as described in the specification, useful as inhibitors of HDAC6. The invention also provides pharmaceutical compositions comprising the compounds of the invention and methods of using the compositions in the treatment of proliferative, inflammatory, infectious, neurological or cardiovascular diseases or disorders.

PRIORITY CLAIM

This application claims the benefit under 35 U.S.C. §119(e) of U.S.Provisional Patent Application Ser. No. 61/219,103, filed Jun. 22, 2009,incorporated by reference in its entirety.

FIELD OF THE INVENTION

The invention relates to compounds and methods for the selectiveinhibition of HDAC6. The present invention relates to compounds usefulas HDAC6 inhibitors. The invention also provides pharmaceuticalcompositions comprising the compounds of the invention and methods ofusing the compositions in the treatment of various diseases.

BACKGROUND OF THE INVENTION

Histone deacetylase 6 (HDAC6) is a member of a family of amidohydrolasescommonly referred to as histone or lysine deacetylases (HDACs or KDACs)as they catalyze the removal of acetyl groups from the ε-amino group oflysine residues from proteins. The family includes 18 enzymes which canbe divided in 3 main classes based on their sequence homology to yeastenzymes Rpd3 (Class I), Hda1 (Class II) and Sir2 (Class III). A fourthclass was defined with the finding of a distinct mammalian enzyme—HDAC11(reviewed in Yang, et al., Nature Rev. Mol. Cell Biol. 2008, 9:206-218and in Saunders and Verdin, Oncogene 2007, 26(37):5489-5504).Biochemically, Class I (HDAC1, 2, 3, 8) and Class II (HDAC4, 5, 6, 7, 9,10) and Class IV (HDAC11) are Zn²⁺-dependent enzymes, while Class III(SIRT1-7) are dependent on nicotinamide adenine dinucleotide (NAD⁺) foractivity. Unlike all other HDACs, HDAC6 resides primarily in thecytosol, it has 2 functional catalytic domains and a carboxy-terminalZn²⁺-finger ubiquitin binding domain that binds ubiquitinated misfoldedproteins (Kawaguchi et al., Cell 2003, 115(6):727-738), ubiquitin(Boyaullt et al., EMBO J. 2006, 25(14): 3357-3366), as well asubiquitin-like FAT10 modifier (Kalveram et al., J. Cell Sci. 2008,121(24):4079-4088). Known substrates of HDAC6 include cytoskeletalproteins α-tubulin and cortactin; β-catenin which forms part of adherensjunctions and anchors the actin cytoskeleton; the chaperone Hsp90; andthe redox regulatory proteins peroxiredoxin (Prx) I and Prx II (reviewedin Boyault et al., Oncogene 2007, 26(37):5468-5476; Matthias et al.,Cell Cycle 2008, 7(1):7-10; Li et al., J Biol. Chem. 2008,283(19):12686-12690; Parmigiani et al., Proc. Natl. Acad. Sci. USA 2009,105(28):9633-9638). Thus, HDAC6 mediates a wide range of cellularfunctions including microtubule-dependent trafficking and signaling,membrane remodeling and chemotactic motility, involvement in control ofcellular adhesion, ubiquitin level sensing, regulation of chaperonelevels and activity, and responses to oxidative stress. All of thesefunctions may be important in tumorigenesis, tumor growth and survivalas well as metastasis (Simms-Waldrip et al., Mol. Genet. Metabolism2008, 94(3):283-286; Rodriguez-Gonzalez et al., Cancer Res. 2008,68(8):2557-2560; Kapoor, Int. J. Cancer 2009, 124:509; Lee et al.,Cancer Res. 2008, 68(18):7561-7569). Recent studies have shown HDAC6 tobe important in autophagy, an alternative pathway for proteindegradation that compensates for deficiencies in the activity of theubiquitin proteasome system or expression of proteins prone to formaggregates and can be activated following treatment with a proteasomeinhibitor (Kawaguchi et al., Cell 2003, 115(6):727-738; Iwata et al., J.Biol. Chem. 2005, 280(48): 40282-40292; Ding et al., Am. J. Pathol.2007, 171:513-524, Pandey et al., Nature 2007, 447(7146):860-864).Although the molecular mechanistic details are not completelyunderstood, HDAC6 binds ubiquitinated or ubiquitin-like conjugatedmisfolded proteins which would otherwise induce proteotoxic stress andthen serves as an adaptor protein to traffic the ubiquitinated cargo tothe microtubule organizing center using the microtubule network via itsknown association with dynein motor protein. The resulting perinuclearaggregates, known as aggresomes, are then degraded by fusion withlysosomes in an HDAC6- and cortactin-dependent process which inducesremodeling of the actin cytoskeleton proximal to aggresomes (Lee et al.,EMBO J. 2010, 29:969-980). In addition, HDAC6 regulates a variety ofbiological processes dependent on its association with the microtubularnetwork including cellular adhesion (Tran et al., J. Cell Sci. 2007,120(8):1469-1479) and migration (Zhang et al., Mol. Cell. 2007,27(2):197-213; reviewed in Valenzuela-Fernandez et al., Trends Cell.Biol. 2008, 18(6):291-297), epithelial to mesenchymal transition (Shanet al., J. Biol. Chem. 2008, 283(30):21065-21073), resistance to anoikis(Lee et al., Cancer Res. 2008, 68(18):7561-7569), epithelial growthfactor-mediated Wnt signaling via β-catenin deacetylation (Li et al., J.Biol. Chem. 2008, 283(19):12686-12690) and epithelial growth factorreceptor stabilization by endocytic trafficking (Lissanu Deribe et al.,Sci. Signal. 2009, 2(102): ra84; Gao et al., J. Biol. Chem. 2010,285:11219-11226); all events that promote oncogenesis and metastasis(Lee et al., Cancer Res. 2008, 68(18):7561-7569). HDAC6 activity isknown to be upregulated by Aurora A kinase in cilia formation (Pugachevaet al., Cell 2007, 129(7):1351-1363) and indirectly by farnesyltransferase with which HDAC6 forms a complex with microtubules (Zhou etal., J. Biol. Chem. 2009, 284(15): 9648-9655). Also, HDAC6 is negativelyregulated by tau protein (Perez et al., J. Neurochem. 2009,109(6):1756-1766).

Diseases in which selective HDAC6 inhibition could have a potentialbenefit include cancer (reviewed in Simms-Waldrip et al., Mol. Genet.Metabolism 2008, 94(3):283-286 and Rodriguez-Gonzalez et al., CancerRes. 2008, 68(8):2557-2560), specifically: multiple myeloma (Hideshimaet al., Proc. Natl. Acad. Sci. USA 2005, 102(24):8567-8572); lung cancer(Kamemura et al., Biochem. Biophys. Res. Commun. 2008, 374(1):84-89);ovarian cancer (Bazzaro et al., Clin. Cancer Res. 2008,14(22):7340-7347); breast cancer (Lee et al., Cancer Res. 2008,68(18):7561-7569); prostate cancer (Mellado et al., Clin. Trans. Onco.2009, 11(1):5-10); pancreatic cancer (Nawrocki et al., Cancer Res. 2006,66(7):3773-3781); renal cancer (Cha et al., Clin. Cancer Res. 2009,15(3):840-850); and leukemias such as acute myeloid leukemia (AML)(Fiskus et al., Blood 2008, 112(7):2896-2905) and acute lymphoblasticleukemia (ALL) (Rodriguez-Gonzalez et al., Blood 2008, 112(11): Abstract1923).

Inhibition of HDAC6 may also have a role in cardiovascular disease, i.e.cardiovascular stress, including pressure overload, chronic ischemia,and infarction-reperfusion injury (Tannous et al., Circulation 2008,117(24):3070-3078); bacterial infection, including those caused byuropathogenic Escherichia coli (Dhakal and Mulve, J. Biol. Chem. 2008,284(1):446-454); neurological diseases caused by accumulation ofintracellular protein aggregates such as Huntington's disease (reviewedin Kazantsev et al., Nat. Rev. Drug Disc. 2008, 7(10):854-868; see alsoDompierre et al., J. Neurosci. 2007, 27(13):3571-3583; Kozikowski etal., J. Med. Chem. 2007, 50:3054-3061) or central nervous system traumacaused by tissue injury, oxidative-stress induced neuronal or axomaldegeneration (Rivieccio et al., Proc. Natl. Acad. Sci. USA 2009,106(46):19599-195604); and inflammation, including reduction ofpro-inflammatory cytokine IL-1β (Carta et al., Blood 2006,108(5):1618-1626), increased expression of the FOXP3 transcriptionfactor, which induces immunosuppressive function of regulatory T-cellsresulting in benefits in chronic diseases such as rheumatoid arthritis,psoriasis, multiple sclerosis, lupus and organ transplant rejection(reviewed in Wang et al., Nat. Rev. Drug Disc. 2009 8(12):969-981).

Given the complex function of HDAC6, selective inhibitors could havepotential utility when used alone or in combination with otherchemotherapeutics such as microtubule destabilizing agents (Zhou et al.,J. Biol. Chem. 2009, 284(15): 9648-9655); Hsp90 inhibitors (Rao et al.,Blood 2008, 112(5)1886-1893); inhibitors of Hsp90 client proteins,including receptor tyrosine kinases such as Her-2 or VEGFR (Bhalla etal., J. Clin. Oncol. 2006, 24(18S): Abstract 1923; Park et al., Biochem.Biophys. Res. Commun. 2008, 368(2):318-322), and signaling kinases suchas Bcr-Abl, Akt, mutant FLT-3, c-Raf, and MEK (Bhalla et al., J. Clin.Oncol. 2006, 24(18S): Abstract 1923; Kamemura et al., Biochem. Biophys.Res. Commun. 2008, 374(1):84-89); inhibitors of cell cycle kinasesAurora A and Aurora B (Pugacheva et al., Cell 2007, 129(7):1351-1363;Park et al., J. Mol. Med. 2008, 86(1):117-128; Cha et al., Clin. CancerRes. 2009, 15(3):840-850); EGFR inhibitors (Lissanu Deribe et al., Sci.Signal. 2009, 2(102): ra84; Gao et al., J. Biol. Chem. E-pub Feb. 4,2010) and proteasome inhibitors (Hideshima et al., Proc. Natl. Acad.Sci. USA 2005, 102(24):8567-8572) or other inhibitors of the ubiquitinproteasome system such as ubiquitin and ubiqutin-like activating (E1),conjugation (E2), ligase enzymes (E3, E4) and deubiquitinase enzymes(DUBs) as well as modulators of autophagy and protein homeostasispathways. In addition, HDAC6 inhibitors could be combined with radiationtherapy (Kim et al., Radiother. Oncol. 2009, 92(1):125-132.

Clearly, it would be beneficial to provide novel HDAC6 inhibitors thatpossess good therapeutic properties, especially for the treatment ofproliferative diseases or disorders.

DETAILED DESCRIPTION OF THE INVENTION

1. General Description of Compounds of the Invention

The present invention provides compounds that are inhibitors of HDAC6,and are useful for the treatment of proliferative diseases or disorders.In one aspect the compounds of the invention are represented by formula(I):

or a pharmaceutically acceptable salt thereof; wherein:

p is 0-2;

q is 1-3;

provided that the total of p and q is 1-3;

G is —R³, —V₁—R³, —V₁-L₁-R³, -L₁-V₂—R³, -L₁-R³, or -L₁-V₂-L₂-R³;

L₁ and L₂ are each independently unsubstituted or substituted C₁₋₃alkylene, where one carbon atom may be replaced with —CR^(A)═CR^(A)—.

V₁ is —C(O)—, —C(S)—, —C(O)—N(R^(4a))—, —C(O)—O—, or —S(O)₂—;

V₂ is —C(O)—, —C(S)—, —N(R^(4a))—, —C(O)—N(R^(4a))—, —N(R^(4a))—C(O)—,—SO₂—N(R^(4a))—, —N(R^(4a))—SO₂—, —C(O)—O—, —O—C(O)—, —O—, —S—, —S(O)—,—S(O)₂—, —N(R^(4a))—C(O)—N(R^(4a))—, —N(R^(4a))—C(O)—O—,—O—C(O)—N(R^(4a))—, or —N(R^(4a))—SO₂—N(R^(4a))—;

R³ is unsubstituted or substituted C₁₋₆ aliphatic, unsubstituted orsubstituted 3-10-membered cycloaliphatic, unsubstituted or substituted4-10-membered heterocyclyl having 1-4 heteroatoms independently selectedfrom nitrogen, oxygen, and sulfur, unsubstituted or substituted6-10-membered aryl, or unsubstituted or substituted 5-10-memberedheteroaryl having 1-5 heteroatoms independently selected from nitrogen,oxygen, and sulfur;

each occurrence of R^(A) is independently hydrogen, halo, orunsubstituted or substituted C₁₋₄aliphatic;

each occurrence of R^(4a) is independently hydrogen, or unsubstituted orsubstituted C₁₋₄ aliphatic;

R¹ is hydrogen, halo, —CN, C₁₋₃ alkyl, C₁₋₃haloalkyl, —O—C₁₋₃ alkyl,—O—C₁₋₃ haloalkyl, —NHC(O)C₁₋₃ alkyl, —NHC(O)NHC₁₋₃ alkyl, orNHS(O)₂C₁₋₃ alkyl;

ring A is optionally further substituted with n occurrences of R²;

each occurrence of R² is independently halo, C₁₋₄ aliphatic, —CN,—OR^(B), —SR^(C), —N(R^(B))₂, —NR^(B)C(O)R^(B), —NR^(B)C(O)N(R^(B))₂,—NR^(B)CO₂R^(C), —CO₂R^(B), —C(O)R^(B), —C(O)N(R^(B))₂, OC(O)N(R^(B))₂,—S(O)₂R^(C), —SO₂N(R^(B))₂, —S(O)R^(C), —NR^(B)SO₂N(R^(B))₂,—NR^(B)SO₂R^(C), or a C₁₋₄ aliphatic substituted with R^(D), halo, —CN,—OR^(B), —SR^(C), —N(R^(B))₂, —NR^(B)C(O)R^(B), —NR^(B)C(O)N(R^(B))₂,—NR^(B)CO₂R^(C), —CO₂R^(B), —C(O)R^(B), —C(O)N(R^(B))₂, —OC(O)N(R^(B))₂,—S(O)₂R^(C), —SO₂N(R^(B))₂, —S(O)R^(C), —NR^(B)SO₂N(R^(B))₂, or—NR^(B)SO₂R^(C); or two R² are taken together to form a 3-6 memberedcycloaliphatic ring;

each occurrence of R^(B) is independently H or C₁₋₄ aliphatic; or twoR^(B) on the same nitrogen atom taken together with the nitrogen atomform a 5-8 membered aromatic or non-aromatic ring having in addition tothe nitrogen atom 0-2 ring heteroatoms selected from N, O and S;

each occurrence of R^(C) is independently C₁₋₄ aliphatic;

each occurrence of R^(D) is independently 6-10-membered aryl, or5-10-membered heteroaryl having 1-5 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur; and n is 0-4.

In another aspect the compounds of the invention are represented byformula (I):

or a pharmaceutically acceptable salt thereof;

wherein:

p is 0-2;

q is 1-3;

provided that the total of p and q is 1-3;

G is —R³, —V₁—R³, —V₁-L₁-R³, -L₁-V₁—R³, -L₂-V₂—R³, —V₁-L₁-V₂—R³, or-L₁-R³;

L₁ is unsubstituted or substituted C₁₋₃ alkylene, where one carbon atommay be replaced with —CR^(A)═CR^(A)—;

L₂ is unsubstituted or substituted C₂₋₃ alkylene, where one carbon atommay be replaced with —CR^(A)═CR^(A)—;

V₁ is —C(O)—, —C(S)—, —C(O)—N(R^(4a))—, —C(O)—O—, or —S(O)₂—;

V₂ is —C(O)—, —C(S)—, —N(R^(4a))—, —C(O)—N(R^(4a))—, —N(R^(4a))—C(O)—,—SO₂—N(R^(4a))—, —N(R^(4a))—SO₂—, —C(O)—O—, —O—C(O)—, —O—, —S—, —S(O)—,—S(O)₂—, —N(R^(4a))—C(O)—N(R^(4a))—, —N(R^(4a))—C(O)—O—,—O—C(O)—N(R^(4a))—, or —N(R^(4a))—SO₂—N(R^(4a))—,

R³ is unsubstituted or substituted C₁₋₆ aliphatic, unsubstituted orsubstituted 3-10-membered cycloaliphatic, unsubstituted or substituted4-10-membered heterocyclyl having 1-4 heteroatoms independently selectedfrom nitrogen, oxygen, and sulfur, unsubstituted or substituted6-10-membered aryl, or unsubstituted or substituted 5-10-memberedheteroaryl having 1-4 heteroatoms independently selected from nitrogen,oxygen, and sulfur;

each occurrence of R^(A) is independently hydrogen, fluoro, orunsubstituted or substituted C₁₋₄ aliphatic;

each occurrence of R^(4a) is independently hydrogen, or unsubstituted orsubstituted C₁₋₄ aliphatic;

R¹ is hydrogen, chloro, fluoro, —O—C₁₋₄ alkyl, cyano, hydroxy, C₁₋₄alkyl, or C₁₋₄ fluoroalkyl;

ring A is optionally further substituted with n occurrences of R²;

each occurrence of R² is independently fluoro, C₁₋₄ alkyl, C₁₋₄haloalkyl, or R^(D); or two R² are taken together to form a 3-6 memberedcycloaliphatic ring;

each occurrence of R^(D) is independently unsubstituted or substituted6-10-membered aryl, or unsubstituted or substituted 5-10-memberedheteroaryl having 1-5 heteroatoms independently selected from nitrogen,oxygen, and sulfur; and

n is 0-4.

2. Compounds and Definitions

Compounds of this invention include those described generally forformula (I) above, and are further illustrated by the classes,subclasses, and species disclosed herein. As used herein, the followingdefinitions shall apply unless otherwise indicated.

As described herein, compounds of the invention may be optionallysubstituted with one or more substituents, such as are illustratedgenerally above, or as exemplified by particular classes, subclasses,and species of the invention. It will be appreciated that the phrase“optionally substituted” is used interchangeably with the phrase“substituted or unsubstituted.” In general, the term “substituted”,whether preceded by the term “optionally” or not, means that a hydrogenradical of the designated moiety is replaced with the radical of aspecified substituent, provided that the substitution results in astable or chemically feasible compound. The term “substitutable”, whenused in reference to a designated atom, means that attached to the atomis a hydrogen radical, which hydrogen atom can be replaced with theradical of a suitable substituent. Unless otherwise indicated, an“optionally substituted” group may have a substituent at eachsubstitutable position of the group, and when more than one position inany given structure may be substituted with more than one substituentselected from a specified group, the substituent may be either the sameor different at every position. Combinations of substituents envisionedby this invention are preferably those that result in the formation ofstable or chemically feasible compounds.

A stable compound or chemically feasible compound is one in which thechemical structure is not substantially altered when kept at atemperature from about −80° C. to about +40°, in the absence of moistureor other chemically reactive conditions, for at least a week, or acompound which maintains its integrity long enough to be useful fortherapeutic or prophylactic administration to a patient.

The phrase “one or more substituents”, as used herein, refers to anumber of substituents that equals from one to the maximum number ofsubstituents possible based on the number of available bonding sites,provided that the above conditions of stability and chemical feasibilityare met.

As used herein, the term “independently selected” means that the same ordifferent values may be selected for multiple instances of a givenvariable in a single compound.

As used herein, the term “aromatic” includes aryl and heteroaryl groupsas described generally below and herein.

The term “aliphatic” or “aliphatic group”, as used herein, means anoptionally substituted straight-chain or branched C₁₋₁₂ hydrocarbon, ora cyclic C₁₋₁₂ hydrocarbon which is completely saturated or whichcontains one or more units of unsaturation, but which is not aromatic(also referred to herein as “carbocycle”, “cycloaliphatic”,“cycloalkyl”, or “cycloalkenyl”). For example, suitable aliphatic groupsinclude optionally substituted linear, branched or cyclic alkyl,alkenyl, alkynyl groups and hybrids thereof, such as (cycloalkyl)alkyl,(cycloalkenyl)alkyl, or (cycloalkyl)alkenyl. Unless otherwise specified,in various embodiments, aliphatic groups have 1-12, 1-10, 1-8, 1-6, 1-4,1-3, or 1-2 carbon atoms.

The term “alkyl”, used alone or as part of a larger moiety, refers to anoptionally substituted straight or branched chain hydrocarbon grouphaving 1-12, 1-10, 1-8, 1-6, 1-4, 1-3, or 1-2 carbon atoms.

The term “alkenyl”, used alone or as part of a larger moiety, refers toan optionally substituted straight or branched chain hydrocarbon grouphaving at least one double bond and having 2-12, 2-10, 2-8, 2-6, 2-4, or2-3 carbon atoms.

The term “alkynyl”, used alone or as part of a larger moiety, refers toan optionally substituted straight or branched chain hydrocarbon grouphaving at least one triple bond and having 2-12, 2-10, 2-8, 2-6, 2-4, or2-3 carbon atoms.

The terms “cycloaliphatic”, “carbocycle”, “carbocyclyl”, “carbocyclo”,or “carbocyclic”, used alone or as part of a larger moiety, refer to anoptionally substituted saturated or partially unsaturated cyclicaliphatic ring system having from 3 to about 14 ring carbon atoms. Insome embodiments, the cycloaliphatic group is an optionally substitutedmonocyclic hydrocarbon having 3-8 or 3-6 ring carbon atoms.Cycloaliphatic groups include, without limitation, optionallysubstituted cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl,cyclohexyl, cyclohexenyl, cycloheptyl, cycloheptenyl, cyclooctyl,cyclooctenyl, or cyclooctadienyl. The terms “cycloaliphatic”,“carbocycle”, “carbocyclyl”, “carbocyclo”, or “carbocyclic” also includeoptionally substituted bridged or fused bicyclic rings having 6-12,6-10, or 6-8 ring carbon atoms, wherein any individual ring in thebicyclic system has 3-8 ring carbon atoms.

The term “cycloalkyl” refers to an optionally substituted saturated ringsystem of about 3 to about 10 ring carbon atoms. Exemplary monocycliccycloalkyl rings include cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, and cycloheptyl.

The term “cycloalkenyl” refers to an optionally substituted non-aromaticmonocyclic or multicyclic ring system containing at least onecarbon-carbon double bond and having about 3 to about 10 carbon atoms.Exemplary monocyclic cycloalkenyl rings include cyclopentyl,cyclohexenyl, and cycloheptenyl.

The terms “haloaliphatic”, “haloalkyl”, “haloalkenyl” and “haloalkoxy”refer to an aliphatic, alkyl, alkenyl or alkoxy group, as the case maybe, which is substituted with one or more halogen atoms. As used herein,the term “halogen” or “halo” means F, Cl, Br, or I. The term“fluoroaliphatic” refers to a haloaliphatic wherein the halogen isfluoro, including perfluorinated aliphatic groups. Examples offluoroaliphatic groups include, without limitation, fluoromethyl,difluoromethyl, trifluoromethyl, 2-fluoroethyl, 2,2,2-trifluoroethyl,1,1,2-trifluoroethyl, 1,2,2-trifluoroethyl, and pentafluoroethyl.

The term “heteroatom” refers to one or more of oxygen, sulfur, nitrogen,phosphorus, or silicon (including, any oxidized form of nitrogen,sulfur, phosphorus, or silicon; the quaternized form of any basicnitrogen or; a substitutable nitrogen of a heterocyclic ring, forexample N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) orNR+ (as in N-substituted pyrrolidinyl)).

The terms “aryl” and “ar-”, used alone or as part of a larger moiety,e.g., “aralkyl”, “aralkoxy”, or “aryloxyalkyl”, refer to an optionallysubstituted C6-14aromatic hydrocarbon moiety comprising one to threearomatic rings. Preferably, the aryl group is a C6-10aryl group. Arylgroups include, without limitation, optionally substituted phenyl,naphthyl, or anthracenyl. The terms “aryl” and “ar-”, as used herein,also include groups in which an aryl ring is fused to one or morecycloaliphatic rings to form an optionally substituted cyclic structuresuch as a tetrahydronaphthyl, indenyl, or indanyl ring. The term “aryl”may be used interchangeably with the terms “aryl group”, “aryl ring”,and “aromatic ring”.

An “aralkyl” or “arylalkyl” group comprises an aryl group covalentlyattached to an alkyl group, either of which independently is optionallysubstituted. Preferably, the aralkyl group is C6-10 arylC1-6alkyl,including, without limitation, benzyl, phenethyl, and naphthylmethyl.

The terms “heteroaryl” and “heteroar-”, used alone or as part of alarger moiety, e.g., “heteroaralkyl”, or “heteroaralkoxy”, refer togroups having 5 to 14 ring atoms, preferably 5, 6, 9, or 10 ring atoms;having 6, 10, or 14 π electrons shared in a cyclic array; and having, inaddition to carbon atoms, from one to five heteroatoms. In someembodiments, the heteroaryl group has 5-10 ring atoms, having, inaddition to carbon atoms, from one to five heteroatoms. A heteroarylgroup may be mono-, bi-, tri-, or polycyclic, preferably mono-, bi-, ortricyclic, more preferably mono- or bicyclic. The term “heteroatom”refers to nitrogen, oxygen, or sulfur, and includes any oxidized form ofnitrogen or sulfur, and any quaternized form of a basic nitrogen. Forexample, a nitrogen atom of a heteroaryl may be a basic nitrogen atomand may also be optionally oxidized to the corresponding N-oxide. When aheteroaryl is substituted by a hydroxy group, it also includes itscorresponding tautomer. The terms “heteroaryl” and “heteroar-”, as usedherein, also include groups in which a heteroaromatic ring is fused toone or more aryl, cycloaliphatic, or heterocycloaliphatic rings.Nonlimiting examples of heteroaryl groups include thienyl, furanyl,pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl,isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl,pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl,naphthyridinyl, pteridinyl, indolyl, isoindolyl, benzothienyl,benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzthiazolyl,quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl,quinoxalinyl, 4H-quinolizinyl, carbazolyl, acridinyl, phenazinyl,phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl,tetrahydroisoquinolinyl, and pyrido[2,3-b]-1,4-oxazin-3(4H)-one. Theterm “heteroaryl” may be used interchangeably with the terms “heteroarylring”, “heteroaryl group”, or “heteroaromatic”, any of which termsinclude rings that are optionally substituted. The term “heteroaralkyl”refers to an alkyl group substituted by a heteroaryl, wherein the alkyland heteroaryl portions independently are optionally substituted.

As used herein, the terms “heterocycle”, “heterocyclyl”, “heterocyclicradical”, and “heterocyclic ring” are used interchangeably and refer toa stable 4-10 membered ring, preferably a 3- to 8-membered monocyclic or7-10-membered bicyclic heterocyclic moiety that is either saturated orpartially unsaturated, and having, in addition to carbon atoms, one ormore, preferably one to four, heteroatoms, as defined above. When usedin reference to a ring atom of a heterocycle, the term “nitrogen”includes a substituted nitrogen. As an example, in a saturated orpartially unsaturated ring having 0-3 heteroatoms selected from oxygen,sulfur or nitrogen, the nitrogen may be N (as in3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl), or NR+ (as inN-substituted pyrrolidinyl).

A heterocyclic ring can be attached to its pendant group at anyheteroatom or carbon atom that results in a stable structure and any ofthe ring atoms can be optionally substituted. Examples of such saturatedor partially unsaturated heterocyclic radicals include, withoutlimitation, tetrahydrofuranyl, tetrahydrothienyl, piperidinyl,decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl,diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, and thiamorpholinyl. Aheterocyclyl group may be mono-, bi-, tri-, or polycyclic, preferablymono-, bi-, or tricyclic, more preferably mono- or bicyclic The term“heterocyclylalkyl” refers to an alkyl group substituted by aheterocyclyl, wherein the alkyl and heterocyclyl portions independentlyare optionally substituted. Additionally, a heterocyclic ring alsoincludes groups in which the heterocyclic ring is fused to one or morearyl rings.

As used herein, the term “partially unsaturated” refers to a ring moietythat includes at least one double or triple bond between ring atoms. Theterm “partially unsaturated” is intended to encompass rings havingmultiple sites of unsaturation, but is not intended to include aromatic(e.g., aryl or heteroaryl) moieties, as herein defined.

The term “alkylene” refers to a bivalent alkyl group. An “alkylenechain” is a polymethylene group, i.e., —(CH₂)_(n′)—, wherein n′ is apositive integer, preferably from 1 to 6, from 1 to 4, from 1 to 3, from1 to 2, or from 2 to 3. An optionally substituted alkylene chain is apolymethylene group in which one or more methylene hydrogen atoms isoptionally replaced with a substituent. Suitable substituents includethose described below for a substituted aliphatic group and also includethose described in the specification herein. It will be appreciated thattwo substituents of the alkylene group may be taken together to form aring system. In certain embodiments, two substituents can be takentogether to form a 3-7-membered ring. The substituents can be on thesame or different atoms.

An alkylene chain also can be optionally interrupted by a functionalgroup. An alkylene chain is “interrupted” by a functional group when aninternal methylene unit is interrupted by the functional group. Examplesof suitable “interrupting functional groups” are described in thespecification and claims herein.

For purposes of clarity, all bivalent groups described herein,including, e.g., the alkylene chain linkers described above, areintended to be read from left to right, with a correspondingleft-to-right reading of the formula or structure in which the variableappears.

An aryl (including aralkyl, aralkoxy, aryloxyalkyl and the like) orheteroaryl (including heteroaralkyl and heteroarylalkoxy and the like)group may contain one or more substituents and thus may be “optionallysubstituted”. In addition to the substituents defined above and herein,suitable substituents on the unsaturated carbon atom of an aryl orheteroaryl group also include and are generally selected from -halo,—NO₂, —CN, —R⁺, —C(R⁺)═C(R⁺)₂, —OR⁺, —SR^(o), —S(O)R^(o), —SO₂R^(o),—SO₃R⁺, —SO₂N(R⁺)₂, —N(R⁺)₂, —NR⁺C(O)R⁺, —NR⁺C(S)R⁺, —NR⁺C(O)N(R⁺)₂,—NR⁺C(S)N(R⁺)₂, —N(R⁺)C(═NR⁺)—N(R⁺)₂, —N(R⁺)C(═NR⁺)—R^(o), —NR⁺CO₂R⁺,—NR⁺SO₂R^(o), —NR⁺SO₂N(R⁺)₂, —O—C(O)R⁺, —O—CO₂R⁺, —OC(O)N(R⁺)₂, —C(O)R⁺,—C(S)R^(o), —CO₂R⁺, —C(O)—C(O)R⁺, —C(O)N(R⁺)₂, —C(S)N(R⁺)₂,—C(O)N(R⁺)—OR⁺, —C(O)N(R⁺)C(═NR⁺)—N(R⁺)₂, —N(R⁺)C(═NR⁺)—N(R⁺)—C(O)R⁺,—C(═NR⁺)—N(R⁺)₂, —C(═NR⁺)—OR⁺, —N(R⁺)—N(R⁺)₂, —C(═NR⁺)—N(R⁺)—OR⁺,—C(R^(o))═N—OR⁺, —P(O)(R⁺)₂, —P(O)(OR⁺)₂, —O—P(O)—OR⁺, and—P(O)(NR⁺)—N(R⁺)₂, wherein R⁺, independently, is hydrogen or anoptionally substituted aliphatic, aryl, heteroaryl, cycloaliphatic, orheterocyclyl group, or two independent occurrences of R⁺ are takentogether with their intervening atom(s) to form an optionallysubstituted 5-7-membered aryl, heteroaryl, cycloaliphatic, orheterocyclyl ring. Each R^(o) is an optionally substituted aliphatic,aryl, heteroaryl, cycloaliphatic, or heterocyclyl group.

An aliphatic or heteroaliphatic group, or a non-aromatic carbycyclic orheterocyclic ring may contain one or more substituents and thus may be“optionally substituted”. Unless otherwise defined above and herein,suitable substituents on the saturated carbon of an aliphatic orheteroaliphatic group, or of a non-aromatic carbocyclic or heterocyclicring are selected from those listed above for the unsaturated carbon ofan aryl or heteroaryl group and additionally include the following: ═O,═S, ═C(R*)₂, ═N—N(R*)₂, ═N—OR*, ═N—NHC(O)R*, ═N—NHCO₂R^(o)═N—NHSO₂R^(o)or ═N—R* where R^(o) is defined above, and each R* is independentlyselected from hydrogen or an optionally substituted C₁₋₆ aliphaticgroup.

In addition to the substituents defined above and herein, optionalsubstituents on the nitrogen of a non-aromatic heterocyclic ring alsoinclude and are generally selected from —R⁺, —N(R⁺)₂, —C(O)R⁺, —C(O)OR⁺,—C(O)C(O)R⁺, —C(O)CH₂C(O)R⁺, —S(O)₂R⁺, —S(O)₂N(R⁺)₂, —C(S)N(R⁺)₂,—C(═NH)—N(R⁺)₂, or —N(R⁺)S(O)₂R⁺; wherein each R⁺ is defined above. Aring nitrogen atom of a heteroaryl or non-aromatic heterocyclic ringalso may be oxidized to form the corresponding N-hydroxy or N-oxidecompound. A nonlimiting example of such a heteroaryl having an oxidizedring nitrogen atom is N-oxidopyridyl.

As detailed above, in some embodiments, two independent occurrences ofR⁺ (or any other variable similarly defined in the specification andclaims herein), are taken together with their intervening atom(s) toform a monocyclic or bicyclic ring selected from 3-13-memberedcycloaliphatic, 3-12-membered heterocyclyl having 1-5 heteroatomsindependently selected from nitrogen, oxygen, or sulfur, 6-10-memberedaryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independentlyselected from nitrogen, oxygen, or sulfur.

Exemplary rings that are formed when two independent occurrences of R⁺(or any other variable similarly defined in the specification and claimsherein), are taken together with their intervening atom(s) include, butare not limited to the following: a) two independent occurrences of R⁺(or any other variable similarly defined in the specification or claimsherein) that are bound to the same atom and are taken together with thatatom to form a ring, for example, N(R⁺)₂, where both occurrences of R⁺are taken together with the nitrogen atom to form a piperidin-1-yl,piperazin-1-yl, or morpholin-4-yl group; and b) two independentoccurrences of R⁺ (or any other variable similarly defined in thespecification or claims herein) that are bound to different atoms andare taken together with both of those atoms to form a ring, for examplewhere a phenyl group is substituted with two occurrences of OR⁺

these two occurrences of R⁺ are taken together with the oxygen atoms towhich they are bound to form a fused 6-membered oxygen containing ring:

It will be appreciated that a variety of other rings (e.g., spiro andbridged rings) can be formed when two independent occurrences of R+ (orany other variable similarly defined in the specification and claimsherein) are taken together with their intervening atom(s) and that theexamples detailed above are not intended to be limiting.

Unless otherwise stated, structures depicted herein are also meant toinclude all isomeric (e.g., enantiomeric, diastereomeric, and geometric(or conformational)) forms of the structure; for example, the R and Sconfigurations for each asymmetric center, (Z) and (E) double bondisomers, and (Z) and (E) conformational isomers. Therefore, singlestereochemical isomers as well as enantiomeric, diastereomeric, andgeometric (or conformational) mixtures of the present compounds arewithin the scope of the invention. Unless otherwise stated, alltautomeric forms of the compounds of the invention are within the scopeof the invention. Additionally, unless otherwise stated, structuresdepicted herein are also meant to include compounds that differ only inthe presence of one or more isotopically enriched atoms. For example,compounds having the present structures except for the replacement ofhydrogen by deuterium or tritium, or the replacement of a carbon by a13C- or 14C-enriched carbon are within the scope of this invention. Suchcompounds are useful, for example, as analytical tools or probes inbiological assays.

The terms “stereoisomer”, “enantiomer”, “diastereomer”, “epimer”, and“chiral center”, are used herein in accordance with the meaning each isgiven in ordinary usage by those of ordinary skill in the art. Thus,stereoisomers are compounds that have the same atomic connectivity, butdiffer in the spatial arrangement of the atoms. Enantiomers arestereoisomers that have a mirror image relationship, that is, thestereochemical configuration at all corresponding chiral centers isopposite. Diastereomers are stereoisomers having more than one chiralcenter, which differ from one another in that the stereochemicalconfiguration of at least one, but not all, of the corresponding chiralcenters is opposite. Epimers are diastereomers that differ instereochemical configuration at only one chiral center.

It is to be understood that, when a disclosed compound has at least onechiral center, the present invention encompasses one enantiomer of thecompound, substantially free from the corresponding optical isomer, aracemic mixture of both optical isomers of the compound, and mixturesenriched in one enantiomer relative to its corresponding optical isomer.When a mixture is enriched in one enantiomer relative to its opticalisomer, the mixture contains, for example, an enantiomeric excess of atleast 50%, 75%, 90%, 95%, 99%, or 99.5%.

The enantiomers of the present invention may be resolved by methodsknown to those skilled in the art, for example by formation ofdiastereoisomeric salts which may be separated, for example, bycrystallization; formation of diastereoisomeric derivatives or complexeswhich may be separated, for example, by crystallization, gas-liquid orliquid chromatography; selective reaction of one enantiomer with anenantiomer-specific reagent, for example enzymatic esterification; orgas-liquid or liquid chromatography in a chiral environment, for exampleon a chiral support for example silica with a bound chiral ligand or inthe presence of a chiral solvent. Where the desired enantiomer isconverted into another chemical entity by one of the separationprocedures described above, a further step is required to liberate thedesired enantiomeric form. Alternatively, specific enantiomers may besynthesized by asymmetric synthesis using optically active reagents,substrates, catalysts or solvents, or by converting one enantiomer intothe other by asymmetric transformation.

When a disclosed compound has at least two chiral centers, the presentinvention encompasses a diastereomer substantially free of otherdiastereomers, an enantiomeric pair of diastereomers substantially freeof other stereoisomers, mixtures of diastereomers, mixtures ofenantiomeric pairs of diastereomers, mixtures of diastereomers in whichone diastereomer is enriched relative to the other diastereomer(s), andmixtures of enantiomeric pairs of diastereomers in which oneenantiomeric pair of diastereomers is enriched relative to the otherstereoisomers. When a mixture is enriched in one diastereomer orenantiomeric pair of diastereomers pairs relative to the otherstereoisomers, the mixture is enriched with the depicted or referenceddiastereomer or enantiomeric pair of diastereomers relative to otherstereoisomers for the compound, for example, by a molar excess of atleast 50%, 75%, 90%, 95%, 99%, or 99.5%.

As used herein, the term “diastereomeric ratio” refers to the ratiobetween diastereomers which differ in the stereochemical configurationat one chiral center, relative to a second chiral center in the samemolecule. By way of example, a chemical structure with two chiralcenters provides four possible stereoisomers: R*R, R*S, S*R, and S*S,wherein the asterisk denotes the corresponding chiral center in eachstereoisomer. The diastereomeric ratio for such a mixture ofstereoisomers is the ratio of one diastereomer and its enantiomer to theother diastereomer and its enantiomer=(R*R+S*S):(R*S+S*R).

One of ordinary skill in the art will recognize that additionalstereoisomers are possible when the molecule has more than two chiralcenters. For purposes of the present invention, the term “diastereomericratio” has identical meaning in reference to compounds with multiplechiral centers as it does in reference to compounds having two chiralcenters. Thus, the term “diastereomeric ratio” refers to the ratio ofall compounds having R*R or S*S configuration at the specified chiralcenters to all compounds having R*S or S*R configuration at thespecified chiral centers. For convenience, this ratio is referred toherein as the diastereomeric ratio at the asterisked carbon, relative tothe second specified chiral center.

The diastereomeric ratio can be measured by any analytical methodsuitable for distinguishing between diastereomeric compounds havingdifferent relative stereochemical configurations at the specified chiralcenters. Such methods include, without limitation, nuclear magneticresonance (NMR), gas chromatography (GC), and high performance liquidchromatography (HPLC) methods.

The diastereoisomeric pairs may be separated by methods known to thoseskilled in the art, for example chromatography or crystallization andthe individual enantiomers within each pair may be separated asdescribed above. Specific procedures for chromatographically separatingdiastereomeric pairs of precursors used in the preparation of compoundsdisclosed herein are provided the examples herein.

3. Description of Exemplary Compounds

In some embodiments, for compounds of formula (I):

V₁ is —C(O)—, —C(O)—N(R^(4a)), or —S(O)₂—;

V₂ is —N(R^(4a))—, —C(O)—N(R^(4a))—, —N(R^(4a))—C(O)—, —SO₂—N(R^(4a))—,—NR^(4a))—SO₂—, —O—, or —S—; and

n is 0-2.

In some embodiments, for compounds of formula (0:

R¹ is hydrogen or methyl;

each occurrence of R² is independently fluoro, methyl, ortrifluoromethyl;

V₁ is —C(O)—, —C(O)—N(R^(4a)), or —S(O)₂—;

V₂ is —C(O)—, —N(R^(4a))—, —C(O)—N(R^(4a))—, —N(R^(4a))—C(O)—,—SO₂—N(R^(4a))—, —N(R^(4a))—SO₂—, —O—, or —S—; and

n is 0-2.

In some embodiments, for compounds of formula (I):

R³ is unsubstituted or substituted C₁₋₆ aliphatic, unsubstituted orsubstituted 3-10-membered cycloaliphatic, unsubstituted or substituted4-10-membered heterocyclyl having 1-4 heteroatoms independently selectedfrom nitrogen, oxygen, and sulfur, unsubstituted or substituted6-10-membered aryl, or unsubstituted or substituted 5-10-memberedheteroaryl having 1-4 heteroatoms independently selected from nitrogen,oxygen, and sulfur; wherein R³ when substituted is substituted with 1-4independent occurrences of —R⁵, wherein R⁵ is —R^(5a), —R^(5d),-T₁-R^(5d), or —V₃-L₃-R^(5d);

each occurrence of R^(5a) is independently halogen, C₁₋₄ aliphatic, —CN,—NO₂, —N(R^(5b))₂, —OR^(5b), —SR^(5c), —S(O)₂R^(5c),—S(O)R^(5c)—C(O)R^(5b), —C(O)OR^(5b), —C(O)N(R^(5b))₂, —S(O)₂N(R^(5b))₂,—OC(O)N(R^(5b))₂, —N(R^(5e))C(O)R^(5b), —N(R^(5e))SO₂R^(5c),—N(R^(5e))C(O)OR^(5b), —N(R^(5e))C(O)N(R^(5b))₂, or—N(R^(5e))SO₂N(R^(5b))₂, or a C₁₋₄ aliphatic substituted with R^(5dd),halogen, —CN, —NO₂, —N(R^(5b))₂, —OR^(5b), —SR^(5c), —S(O)₂R^(5c),—S(O)R^(5c)—C(O)R^(5b), —C(O)OR^(5b), —C(O)N(R^(5b))₂, —S(O)₂N(R^(5b))₂,—OC(O)N(R^(5b))₂, —N(R^(5e))C(O)R^(5b), —N(R^(5e))SO₂R^(5c),—N(R^(5e))C(O)OR^(5b), —N(R^(5e))C(O)N(R^(5b))₂, or—N(R^(5e))SO₂N(R^(5b))₂;

each occurrence of R^(5b) is independently hydrogen or an optionallysubstituted group selected from C₁₋₆ aliphatic, 3-10-memberedcycloaliphatic, 4-10-membered heterocyclyl having 1-4 heteroatomsindependently selected from nitrogen, oxygen, and sulfur, 6-10-memberedaryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independentlyselected from nitrogen, oxygen, and sulfur; or two occurrences of R^(5b)on the same nitrogen atom can be taken together with the nitrogen atomto which they are bound to form an optionally substituted 4-7-memberedheterocyclyl ring having 0-1 additional heteroatoms selected fromnitrogen, oxygen, and sulfur;

each occurrence of R^(5e) is independently an optionally substitutedgroup selected from C₁₋₆ aliphatic, 3-10-membered cycloaliphatic,4-10-membered heterocyclyl having 1-4 heteroatoms independently selectedfrom nitrogen, oxygen, and sulfur, 6-10-membered aryl, or 5-10-memberedheteroaryl having 1-5 heteroatoms independently selected from nitrogen,oxygen, and sulfur;

each occurrence of R^(5d) is an optionally substituted group selectedfrom 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5heteroatoms independently selected from nitrogen, oxygen, and sulfur;

each occurrence of R^(5dd) is an optionally substituted group selectedfrom 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5heteroatoms independently selected from nitrogen, oxygen, and sulfur;

each occurrence of R^(5e) is independently hydrogen or an optionallysubstituted C₁₋₆ aliphatic group;

each occurrence of V₃ is independently —N(R^(5e)), —O—, —S—, —S(O)—,—S(O)₂—, —C(O)—, —C(O)O—, —C(O)R^(5e))—, —S(O)₂N(R^(5e))—,—OC(O)N(R^(5e))—, —N(R^(5e))C(O)—, —N(R^(5e))SO₂—, —N(R^(5e))C(O)O—,—N(R^(5e))C(O)N(R^(5e))—, —N(R^(5e))SO₂N(R^(5e))—, —OC(O)—, or—C(O)N(R^(5e))O—; and

L₃ is an optionally substituted C₁₋₃ alkylene chain, where one carbonatom may be replaced with —CR^(A)═CR^(A)—.

In some embodiments, compounds of formula (I) are represented byformulas (II-A)-(II-F):

wherein R¹, R², G, and n have the values described herein.

In some embodiments, compounds of formula (I) are represented byformulas (II-A), (II-B), or (II-C). In some embodiments, compounds offormula (I) are represented by formulas (II-A), or (II-B). In certainembodiments, compounds of formula (I) are represented by formula (II-A).In certain embodiments, compounds of formula (I) are represented byformula (II-B).

In some embodiments, compounds of formula (I) are represented byformulas (III-A)-(III-F):

wherein G, and R¹ have the values described herein.

In some embodiments, compounds of formula (I) are represented byformulas (III-A), (III-B), or (III-C). In some embodiments, compounds offormula (I) are represented by formulas (III-A), or (III-B). In certainembodiments, compounds of formula (I) are represented by formula(III-A). In certain embodiments, compounds of formula (I) arerepresented by formula (III-B).

In some embodiments, compounds of formula (I) are represented byformulas (IV-A)-(IV-C):

wherein G has the values described herein.

In certain embodiments, compounds of formula (I) are represented byformula (IV-A). In certain embodiments, compounds of formula (I) arerepresented by formula (IV-B). In certain embodiments, compounds offormula (I) are represented by formula (IV-C).

In some embodiments, compounds of formula (I) are represented byformulas (V-A)-(V-G):

wherein R³, R⁶, R⁶′, p, q, and V_(2a) have the values described herein.

In certain embodiments, compounds of formula (I) are represented byformula (V-A). In certain embodiments, compounds of formula (I) arerepresented by formula (V-B). In certain embodiments, compounds offormula (I) are represented by formula (V-C). In certain embodiments,compounds of formula (I) are represented by formula (V-D). In certainembodiments, compounds of formula (I) are represented by formula (V-E).In certain embodiments, compounds of formula (I) are represented byformula (V-F). In certain embodiments, compounds of formula (I) arerepresented by formula (V-G).

The values described below are with respect to any of formulas (I),(II-A)-(II-G), (III-A)-(III-G), (IV-A)-(IV-B) and (V-A)-(V-G).

In some embodiments:

p is 0-2;

q is 1-3;

provided that the total of p and q is 1-3.

In certain embodiments, p is 1 and q is 1. In certain embodiments, p is0 and q is 1. In certain embodiments, p is 0 and q is 2. In certainembodiments, p is 1 and q is 2. In certain embodiments, p is 2 and qis 1. In certain embodiments, p is 0 and q is 3.

In some embodiments, R¹ is hydrogen, halo, —CN, C₁₋₃ alkyl,C₁₋₃haloalkyl, —O—C₁₋₃ alkyl, —O—C₁₋₃ haloalkyl, —NHC(O)C₁₋₃ alkyl,—NHC(O)NHC₁₋₃ alkyl, or NHS(O)₂C₁₋₃ alkyl. In some embodiments, R¹ ishydrogen, chloro, fluoro, —O—C₁₋₄ alkyl, cyano, hydroxy, C₁₋₄ alkyl, orC₁₋₄ fluoroalkyl. In certain embodiments, R¹ is hydrogen, chloro,fluoro, methoxy, ethoxy, propoxy, cyano, trifluoromethyl, methyl, ethyl,n-propyl, isopropyl, or tert-butyl. In certain embodiments, R¹ ishydrogen, chloro, fluoro, methoxy, cyano, or methyl. In certainembodiments, R¹ is hydrogen or methyl. In certain embodiments, R¹ ishydrogen. In certain embodiments, R¹ is methyl.

In some embodiments, ring A is optionally further substituted with noccurrences of R² wherein, each occurrence of R² is independently halo,C₁₋₄ aliphatic, —CN, —OR^(B), —SR^(C), —N(R^(B))₂, —NR^(B)C(O)R^(B),—NR^(B)C(O)N(R^(B))₂, C(O)N(R^(B))₂, —NR^(B)CO₂R^(C), —CO₂R^(B),—C(O)R^(B), —C(O)N(R^(B))₂, —OC(O)N(R^(B))₂, —S(O)₂R^(C), —SO₂N(R^(B))₂,—S(O)R^(C), —NR^(B)SO₂N(R^(B))₂, —NR^(B)SO₂R^(C), or a C₁₋₄ aliphaticsubstituted with R^(D), halo, —CN, —OR^(B), —SR^(C), —N(R^(B))₂,—NR^(B)C(O)R^(B), —NR^(B)C(O)N(R^(B))₂, —NR^(B)CO₂R^(C), —CO₂R^(B),—C(O)R^(B), —C(O)N(R^(B))₂, —OC(O)N(R^(B))₂, —S(O)₂R^(C), —SO₂N(R^(B))₂,—S(O)R^(C), —NR^(B)SO₂N(R^(B))₂, or —NR^(B)SO₂R^(C). In someembodiments, two R² are taken together to form a 3-6 memberedcyclaliphatic ring. In some embodiments, each occurrence of R² isindependently halo, C₁₋₃ alkyl, C₁₋₃haloalkyl, —O—C₁₋₃ alkyl, —O—C₁₋₃haloalkyl, —NHC(O)C₁₋₃ alkyl, —NHC(O)NHC₁₋₃ alkyl, NHS(O)₂C₁₋₃ alkyl, orC₁₋₄aliphatic optionally substituted with R^(D). In certain embodiments,each occurrence of R² is independently chloro, fluoro, methoxy, ethoxy,propoxy, trifluoromethyl, methyl, ethyl, n-propyl, isopropyl, ortert-butyl.

In some embodiments, each occurrence of R² is independently fluoro,C₁₋₄alkyl, C₁₋₄haloalkyl, —NHC(O)C₁₋₆ alkyl, —NHC(O)NHC₁₋₆ alkyl,NHS(O)₂C₁₋₆ alkyl, or R^(D), wherein R^(D) has the values containedherein. In some embodiments, each occurrence of R² is independentlyfluoro, C₁₋₄ alkyl, C₁₋₄haloalkyl, or R^(D), wherein R^(D) has thevalues contained herein. In some embodiments each occurrence of R² isindependently fluoro, C₁₋₄ alkyl, C₁₋₄haloalkyl, or phenyl, wherein thephenyl ring is unsubstituted or substituted with one occurrence offluoro, chloro, or methyl. In some embodiments, each occurrence of R² isindependently fluoro, methyl, or trifluoromethyl. In certainembodiments, each occurrence of R² is independently methyl or fluoro. Incertain embodiments, R² is methyl.

In some embodiments, each occurrence of R^(B) is independently H or C₁₋₄aliphatic; or two R^(B) on the same nitrogen atom taken together withthe nitrogen atom form a 5-8 membered aromatic or non-aromatic ringhaving in addition to the nitrogen atom 0-2 ring heteroatoms selectedfrom N, O and S.

In some embodiments, each occurrence of R^(C) is independently C₁₋₄aliphatic.

In some embodiments, each occurrence of R^(D) is independently6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatomsindependently selected from nitrogen, oxygen, and sulfur.

In some embodiments, n is 0-4. In some embodiments, n is 0-2. In certainembodiments, n is 2. In certain embodiments, n is 1. In certainembodiments, n is 0.

In some embodiments, G is —R³, —V₁—R³, —V₁-L₁-R³, -L₁-V₂—R³, -L₁-R³, or-L₁-V₂-L₂-R³, wherein L₁, L₂, V₁, V₂, and R³ have the values describedherein. In some embodiments, G is —R³, —V₁—R³, —V₁-L₁-R³, -L₁-V₁—R³,-L₂-V₂—R³, —V₁-L₁-V₂—R³, or -L₁-R³, wherein L₁, L₂, V₁, V₂, and R³ havethe values described herein. In some embodiments, G is —R³, —V₁—R³, or-L₁-R³, wherein L₁, V₁, and R³ have the values described herein.

In certain embodiments, G is —R³, —C(R⁶)(R^(6′))—R³, —C(O)—R³, or—S(O)₂—R³, wherein R³, R⁶, and R^(6′) have the values described herein.In certain embodiments, G is —R³, wherein R³ has the values describedherein. In certain embodiments, G is —(CH₂)_(t)—R³, or —(CH₂)_(n)—X₃—R³,wherein R³, X₃ and t have the values described herein. In certainembodiments, G is —C(O)—R³, —C(R⁶)(R^(6′))—R³, —C(O)—C(R⁶)(R^(6′))—R³,—S(O)₂—R³, —S(O)₂—C(R⁶)(R^(6′))—R³, or —C(O)—NH—R³, wherein R³, R⁶ andR^(6′) have the values described herein. In certain embodiments, G is—CH₂—CH═CH—R³, wherein R³ has the values described herein.

In certain embodiments, G is —[C(R⁶)(R^(6′))]_(z)—R³,—C(O)—[C(R⁶)(R^(6′))]_(z)—R³, —C(O)—N(R^(4a))—[C(R⁶)(R^(6′))]_(z)—R³,—S(O)₂—[C(R⁶)(R^(6′))]_(z)—R³, —[C(R⁶)(R^(6′))]_(y)—V_(2a)—R³,—C(O)—[C(R⁶)(R^(6′))]_(y)—V_(2a)—R³, —C(R⁶)(R^(6′))—V_(2a′)—R³, or—C(O)—C(R⁶)(R^(6′))—V_(2a′)—R³, wherein R⁶, R^(6′), V_(2a), V_(2a′), R³,R^(4a), z, and y have the values described herein. In certainembodiments, G is —[C(R⁶)(R^(6′))]_(z)—R³, —C(O)—[C(R⁶)(R^(6′))]_(z)—R³,—C(O)—NH—[C(R⁶)(R^(6′))]_(z)—R³, —S(O)₂—[C(R⁶)(R^(6′))]_(z)—R³,—[C(R⁶)(R^(6′))]_(y)—V_(2a)—R³, —C(O)—[C(R⁶)(R^(6′))]_(y)—V_(2a)—R³,—C(R⁶)(R^(6′))—V_(2a′)—R³, or —C(O)—C(R⁶)(R^(6′))—V_(2a′)—R³, whereinR⁶, R^(6′), V_(2a), V_(2a′), R³, z, and y have the values describedherein. In certain embodiments, G is —[C(R⁶)(R^(6′))]_(z)—R³,—C(O)—[C(R⁶)(R^(6′))]_(z)—R³, or —S(O)₂—[C(R⁶)(R^(6′))]_(z)—R³, whereinR⁶, R^(6′), R³, and z have the values described herein.

In some embodiments, L₁ and L₂ are each independently unsubstituted orsubstituted C₁₋₃ alkylene, where one carbon atom may be replaced with—CR^(A)═CR^(A)—. In some embodiments, L₁ and L₂ are each independently—CH₂—, CH₂CH₂—, —CH₂CH₂CH₂—, or —CH═CH—. In some embodiments, L₁ and L₂are each independently —CH₂—. In some embodiments, L₁ and L₂ are eachindependently a C₁₋₃ alkylene chain, where one carbon atom may bereplaced with —CR^(A)═CR^(A)—, optionally substituted with 0-2occurrences of R^(8a) wherein each occurrence of R^(8a) is independentlyhalogen, C₁₋₄ aliphatic, —CN, —NO₂, —N(R^(5b))₂, —OR^(5c), —SR^(5c),—S(O)₂R^(5c), —S(O)R^(5c), —C(O)R^(5b), —C(O)OR^(5b), —C(O)N(R^(5b))₂,—S(O)₂N(R^(5b))₂, —OC(O)N(R^(5b))₂, —N(R^(5e))C(O)R^(5b),—N(R^(5e))SO₂R^(5c), —N(R^(5e))C(O)OR^(5b), —N(R^(5e))C(O)N(R^(5b))₂, or—N(R^(5e))SO₂N(R^(5b))₂; or a C₁₋₄ aliphatic substituted with halogen,—CN, —NO₂, —N(R^(5b))₂, —OR^(5b), —SR^(5c), —S(O)₂R^(5c), —S(O)R^(5c),—C(O)R^(5b), —C(O)OR^(5b), —C(O)N(R^(5b))₂, —S(O)₂N(R^(5b))₂,—OC(O)N(R^(5b))₂, —N(R^(5e))C(O)R^(5b), —N(R^(5e))SO₂R^(5e),—N(R^(5e))C(O)OR^(5b), —N(R^(5e))C(O)N(R^(5b))₂, or—N(R^(5e))SO₂N(R^(5b))₂. In some embodiments, L₁ and L₂ are eachindependently a C₁₋₃ alkylene chain, where one carbon atom may bereplaced with —CR^(A)═CR^(A)—, optionally substituted with 0-2occurrences of R^(8a) wherein each occurrence of R^(8a) is independentlyfluoro or C₁₋₄ aliphatic.

In some embodiments, L₂ is unsubstituted or substituted C₂₋₃ alkylene,where one carbon atom may be replaced with —CR^(A)═CR^(A)—. In someembodiments, L₂ is —CH₂CH₂— or —CH₂CH₂CH₂—. In certain embodiments, L₂is —CH₂CH₂—. In certain embodiments, L₂ is —CH₂CH₂CH₂—.

In some embodiments, V₁ is —C(O)—, —C(S)—, —C(O)—N(R^(4a))—, —C(O)—O—,or —S(O)₂—, wherein R^(4a) has the values described herein. In someembodiments, V₁ is —C(O)—, —C(O)—N(R^(4a))—, or S(O)₂—, wherein R^(4a)has the values described herein. In certain embodiments, V₁ is —C(O)—,—C(O)—NH—, or S(O)₂—. In certain embodiments, V₁ is —C(O)—, or S(O)₂—.

In some embodiments, V₂ is —C(O)—, —C(S)—, —N(R^(4a))—,—C(O)—N(R^(4a))—, —N(R^(4a))—C(O)—, —SO₂—N(R^(4a))—, —N(R^(4a))—SO₂—,—C(O)—O—, —O—C(O)—, —O—, —S—, —S(O)—, —S(O)₂—,—N(R^(4a))—C(O)—N(R^(4a))—, —N(R^(4a))—C(O)—O—, —O—C(O)—N(R^(4a))—, or—N(R^(4a))—SO₂—N(R^(4a))—, wherein R^(4a) has the values describedherein. In some embodiments, V₂ is —C(O)—, —N(R^(4a))—,—C(O)—N(R^(4a))—, —N(R^(4a))—C(O)—, —SO₂—N(R^(4a))—, —N(R^(4a))—SO₂—,—O—, or —S—. In certain embodiments, V₂ is —C(O)—, —N(R^(4a))—, —O—, or—S—. In certain embodiments, V₂ is —NH—, or —O—.

In some embodiments, each occurrence of R^(A) is independently hydrogen,halo, or an unsubstituted or substituted C₁₋₄aliphatic. In someembodiments, each occurrence of R^(A) is independently hydrogen, fluoro,or unsubstituted or substituted C₁₋₄ aliphatic. In certain embodiments,each occurrence of R^(A) is independently hydrogen, fluoro or methyl. Incertain embodiments, each occurrence of R^(A) is hydrogen.

In some embodiments, each occurrence of R^(4a) is independentlyhydrogen, or unsubstituted or substituted C₁₋₄aliphatic. In some otherembodiments, each occurrence of R^(4a) is independently hydrogen.

In some embodiments, G is represented by formulas (VI-a-i)-(VI-n-v):

In some embodiments, R³ is unsubstituted or substituted C₁₋₆ aliphatic,unsubstituted or substituted 3-10-membered cycloaliphatic, unsubstitutedor substituted 4-10-membered heterocyclyl having 1-4 heteroatomsindependently selected from nitrogen, oxygen, and sulfur, unsubstitutedor substituted 6-10-membered aryl, or unsubstituted or substituted5-10-membered heteroaryl having 1-5 heteroatoms independently selectedfrom nitrogen, oxygen, and sulfur.

In certain embodiments, R³ is methyl, ethyl, propyl, isopropyl,tert-butyl, butyl, iso-butyl, pentyl, hexyl, butenyl, propenyl,pentenyl, hexenyl, furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl,imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl,thiadiazolyl, phenyl, naphthyl, pyranyl, pyridyl, pyridazinyl,pyrimidinyl, pyrazinyl, triazinyl, indolizinyl, imidazopyridyl, indolyl,isoindolyl, indazolyl, benzimidazolyl, benzthiazolyl, benzothienyl,benzofuranyl, benzoxazolyl, benzodioxolyl, benzthiadiazolyl,2,3-dihydrobenzofuranyl, 4H-furo[3,2-b]pyrrolyl, pyrazolopyrimidinyl,purinyl, quinolyl, isoquinolyl, tetrahydroquinolinyl,tetrahydronaphthyridinyl, tetrahydroisoquinolinyl, cinnolinyl,phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, pteridinyl,tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothienyl, indanyl,tetrahydroindazolyl, pyrrolidinyl, pyrrolidonyl, piperidinyl,pyrrolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl,diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, thiomorpholinyl,quinuclidinyl, phenanthridinyl, tetrahydronaphthyl, indolinyl,benzodioxanyl, chromanyl, cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl, cyclooctyl, cyclopentenyl, cyclohexenyl,cycloheptenyl, cyclooctenyl, bicycloheptanyl, bicyclooctanyl, oradamantyl, wherein each of the foregoing groups are unsubstituted orsubstituted.

In some embodiments, R³ is unsubstituted or substituted C₁₋₆, aliphatic,unsubstituted or substituted 3-10-membered cycloaliphatic, unsubstitutedor substituted 4-10-membered heterocyclyl having 1-4 heteroatomsindependently selected from nitrogen, oxygen, and sulfur, unsubstitutedor substituted 6-10-membered aryl, or unsubstituted or substituted5-10-membered heteroaryl having 1-5 heteroatoms independently selectedfrom nitrogen, oxygen, and sulfur, wherein if R³ is substituted, it issubstituted with 1-4 independent occurrences of —R⁵, wherein R⁵ is—R^(5a), —R^(5d), -L₃-R^(5d), or —V₃-L₃-R^(5d); and R^(5a), R^(5d), L₃,and V₃ have the values described herein.

In certain embodiments, R³ is methyl, ethyl, propyl, isopropyl,tert-butyl, butyl, iso-butyl, pentyl, hexyl, butenyl, propenyl,pentenyl, hexenyl, furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl,imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl,thiadiazolyl, phenyl, naphthyl, pyranyl, pyridyl, pyridazinyl,pyrimidinyl, pyrazinyl, triazinyl, indolizinyl, imidazopyridyl, indolyl,isoindolyl, indazolyl, benzimidazolyl, benzthiazolyl, benzothienyl,benzofuranyl, benzoxazolyl, benzodioxolyl, benzthiadiazolyl,2,3-dihydrobenzofuranyl, 4H-furo[3,2-b]pyrrolyl, pyrazolopyrimidinyl,purinyl, quinolyl, isoquinolyl, tetrahydroquinolinyl,tetrahydronaphthyridinyl, tetrahydroisoquinolinyl, cinnolinyl,phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, pteridinyl,tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothienyl, indanyl,tetrahydroindazolyl, pyrrolidinyl, pyrrolidonyl, piperidinyl,pyrrolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl,diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, thiomorpholinyl,quinuclidinyl, phenanthridinyl, tetrahydronaphthyl, indolinyl,benzodioxanyl, chromanyl, cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl, cyclooctyl, cyclopentenyl, cyclohexenyl,cycloheptenyl, cyclooctenyl, bicycloheptanyl, bicyclooctanyl, oradamantyl, wherein each of the foregoing groups are unsubstituted orsubstituted with 1-4 independent occurrences of —R⁵, wherein R⁵ is—R^(5a), —R^(5d), -L₃-R^(5d), or —V₃-L₃-R^(5d); and R^(5a), R^(5d), L₃,and V₃ have the values described herein.

In some embodiments, R³ is —R^(3a), wherein R^(3a) is unsubstituted orsubstituted 6-10-membered aryl, or unsubstituted or substituted5-10-membered heteroaryl having 1-5 heteroatoms independently selectedfrom nitrogen, oxygen, and sulfur; wherein R^(3a) if substituted issubstituted with 0-1 occurrences of —R^(5a), and one occurrence of—R^(5d), wherein R^(5a) and R^(5d) have the values described herein.

In some embodiments, R^(3a) is furanyl, thienyl, pyrrolyl, oxazolyl,thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl,triazolyl, thiadiazolyl, phenyl, naphthyl, pyranyl, pyridyl,pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, indolizinyl, indolyl,isoindolyl, indazolyl, benzimidazolyl, benzthiazolyl, benzothienyl,benzofuranyl, benzoxazolyl, benzo[c][1,2,5]oxadiazolyl,benzo[c][1,2,5]thiadiazolyl, benzo[d]oxazol-2(3H)-one,2,3-dihydrobenzo[b][1,4]dioxinyl, benzo[d][1,3]dioxolyl,2,3-dihydrobenzofuranyl, 4H-furo[3,2-b]pyrrolyl, purinyl, quinolyl,isoquinolyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, cinnolinyl,phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, or pteridinyl,wherein each of the foregoing groups is unsubstituted or substitutedwith 0-1 occurrences of —R^(5a), and 1 occurrence of —R^(5d), whereinR^(5a) and R^(5d) have the values described herein. In certainembodiments, R^(3a) is thienyl, thiazolyl, pyrazolyl, isoxazolyl,oxadiazolyl, 4H-furo[3,2-b]pyrrolyl, or phenyl, wherein each of theforegoing groups is unsubstituted or substituted with 0-1 occurrences of—R^(5a), and 1 occurrence of —R^(5d), wherein R^(5a) and R^(5d) have thevalues described herein.

In some embodiments, R³ is —R^(3b), wherein R^(3b) is unsubstituted orsubstituted 6-10-membered aryl, or unsubstituted or substituted5-10-membered heteroaryl having 1-5 heteroatoms independently selectedfrom nitrogen, oxygen, and sulfur; wherein R^(3b) if substituted issubstituted with 0-2 independent occurrences of —R^(5a), wherein R^(5a)has the values described herein. In some embodiments, R^(3b) is furanyl,thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl,isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, phenyl,naphthyl, pyranyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl,triazinyl, indolizinyl, indolyl, isoindolyl, indazolyl, benzimidazolyl,benzthiazolyl, benzothienyl, benzofuranyl, benzoxazolyl,benzo[c][1,2,5]oxadiazolyl, benzo[c][1,2,5]thiadiazolyl,benzo[d]oxazol-2(3H)-one, 2,3-dihydrobenzo[b][1,4]dioxinyl,benzo[d][1,3]dioxolyl, 2,3-dihydrobenzofuranyl, 4H-furo[3,2-b]pyrrolyl,purinyl, quinolyl, isoquinolyl, tetrahydroquinolinyl,tetrahydroisoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl,quinoxalinyl, naphthyridinyl, or pteridinyl, wherein each of theforegoing groups is unsubstituted or substituted with 0-1 occurrence of—R^(5a), wherein R^(5a) has the values described herein.

In some embodiments, R³ is —R^(3c), wherein R^(3c) is unsubstituted orsubstituted 6-10-membered aryl, unsubstituted or substituted4-10-membered heterocyclyl having 1-4 heteroatoms independently selectedfrom nitrogen, oxygen, and sulfur, or unsubstituted or substituted5-10-membered heteroaryl having 1-5 heteroatoms independently selectedfrom nitrogen, oxygen, and sulfur, wherein R^(3c) if substituted issubstituted with 0-2 independent occurrences of —R^(5a), wherein R^(5a)has the values described herein. In some embodiments, R^(3c) is furanyl,thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl,isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, phenyl,naphthyl, pyranyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl,triazinyl, indolizinyl, indolyl, isoindolyl, indazolyl, benzimidazolyl,benzthiazolyl, benzothienyl, benzofuranyl, benzoxazolyl,benzo[c][1,2,5]oxadiazolyl, benzo[c][1,2,5]thiadiazolyl,benzo[d]oxazol-2(3H)-one, 2,3-dihydrobenzo[b][1,4]dioxinyl,benzo[d][1,3]dioxolyl, 2,3-dihydrobenzofuranyl, 4H-furo[3,2-b]pyrrolyl,purinyl, quinolyl, isoquinolyl, tetrahydroquinolinyl,tetrahydroisoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl,quinoxalinyl, naphthyridinyl, pteridinyl, tetrahydrofuranyl,tetrahydrothienyl, pyrrolidinyl, pyrrolidonyl, piperidinyl, pyrrolinyl,decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl,diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, thiamorpholinyl,quinuclidinyl, indanyl, phenanthridinyl, tetrahydronaphthyl, indolinyl,benzodioxanyl, benzodioxolyl, or chromanyl, wherein each of theforegoing groups is unsubstituted or substituted with 0-2 independentoccurrences of —R^(5a), wherein R^(5a) has the values described herein.In certain embodiments, R^(3c) is phenyl, naphthyl or indolyl, whereineach of the foregoing groups is unsubstituted or substituted with 0-1independent occurrences of —R^(5a), wherein R^(5a) has the valuesdescribed herein.

In some embodiments, R³ is —R^(3d), wherein R^(3d) is unsubstituted orsubstituted C₁₋₆ aliphatic, unsubstituted or substituted 3-10-memberedcycloaliphatic, unsubstituted or substituted 4-10-membered heterocyclylhaving 1-4 heteroatoms independently selected from nitrogen, oxygen, andsulfur, unsubstituted or substituted 6-10-membered aryl, orunsubstituted or substituted 5-10-membered heteroaryl having 1-5heteroatoms independently selected from nitrogen, oxygen, and sulfur,wherein R^(3d) if substituted is substituted with 0-2 independentoccurrences of —R^(5a), wherein R^(5a) has the values described herein.

In some embodiments, R^(3d) is unsubstituted or substituted C₁₋₆aliphatic, wherein R^(3d) if substituted is substituted with 0-1independent occurrences of —R^(5a), wherein R^(5a) has the valuesdescribed herein. In certain embodiments, R^(3d) is methyl, ethyl,propyl, isopropyl, tert-butyl, butyl, iso-butyl, pentyl, hexyl, butenyl,propenyl, pentenyl, or hexenyl.

In some embodiments, R^(3d) is unsubstituted or substituted3-10-membered cycloaliphatic, unsubstituted or substituted 4-10-memberedheterocyclyl having 1-4 heteroatoms independently selected fromnitrogen, oxygen, and sulfur, unsubstituted or substituted 6-10-memberedaryl, or unsubstituted or substituted 5-10-membered heteroaryl having1-5 heteroatoms independently selected from nitrogen, oxygen, andsulfur, wherein R^(3d) if substituted is substituted with 0-2independent occurrences of —R^(5a), wherein R^(5a) has the valuesdescribed herein. In certain embodiments, R^(3d) is furanyl, thienyl,pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl,isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, phenyl, naphthyl,pyranyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl,indolizinyl, indolyl, isoindolyl, indazolyl, benzimidazolyl,benzthiazolyl, benzothienyl, benzofuranyl, benzoxazolyl,benzo[c][1,2,5]oxadiazolyl, benzo[c][1,2,5]thiadiazolyl,benzo[d]oxazol-2(3H)-one, 2,3-dihydrobenzo[b][1,4]dioxinyl,benzo[d][1,3]dioxolyl, 2,3-dihydrobenzofuranyl, 4H-furo[3,2-b]pyrrolyl,purinyl, quinolyl, isoquinolyl, tetrahydroquinolinyl,tetrahydroisoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl,quinoxalinyl, naphthyridinyl, pteridinyl, tetrahydrofuranyl,tetrahydrothienyl, pyrrolidinyl, pyrrolidonyl, piperidinyl, pyrrolinyl,decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl,diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, thiamorpholinyl,quinuclidinyl, indanyl, phenanthridinyl, tetrahydronaphthyl, indolinyl,benzodioxanyl, benzodioxolyl, chromanyl, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopentenyl,cyclohexenyl, cycloheptenyl, cyclooctenyl, bicycloheptanyl,bicyclooctanyl, or adamantyl, wherein each of the foregoing groups isunsubstituted or substituted with 0-2 independent occurrences of—R^(5a), wherein R^(5a) has the values described herein.

In certain embodiments, R^(3d) is pyrrolyl, thiazolyl, imidazolyl,pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, phenyl, pyridyl,indolyl, benzimidazolyl, benzthiazolyl, benzoxazolyl,benzo[c][1,2,5]oxadiazolyl, benzo[c][1,2,5]thiadiazolyl,benzo[d]oxazol-2(3H)-one, 2,3-dihydrobenzo[b][1,4]dioxinyl,benzo[d][1,3]dioxolyl, 2,3-dihydrobenzofuranyl, purinyl, quinolyl,cinnolinyl, naphthyl, piperidinyl, cyclopropyl, cyclopentyl, cyclohexyl,cycloheptyl, cyclohexenyl, or adamantyl, wherein each of the foregoinggroups is unsubstituted or substituted with 0-1 independent occurrencesof —R^(5a), wherein R^(5a) has the values described herein.

In some embodiments, each occurrence of R^(5a) is independently halogen,C₁₋₄ aliphatic, —CN, —NO₂, —N(R^(5b))₂, —OR^(5b), —SR^(5c),—S(O)₂R^(5c), —S(O)R^(5c), —C(O)R^(5b), —C(O)OR^(5b), —C(O)N(R^(5b))₂,—S(O)₂N(R^(5b))₂, —OC(O)N(R^(5b))₂, —N(R^(5e))C(O)R^(5b),—N(R^(5e))SO₂R^(5c), —N(R^(5e))C(O)OR^(5b), —N(R^(5e))C(O)N(R^(5b))₂, or—N(R^(5e))SO₂N(R^(5b))₂, or a C₁₋₄ aliphatic substituted with R^(5dd),halogen, —CN, —NO₂, —N(R^(5b))₂, —OR^(5b), —SR^(5c), —S(O)₂R^(5c),—S(O)R^(5c), —C(O)R^(5b), —C(O)OR^(5b), —C(O)N(R^(5b))_(z),—S(O)₂N(R^(5b))₂, —OC(O)N(R^(5b))₂, —N(R^(5e))C(O)R^(5b),—N(R^(5e))SO₂R^(5c), —N(R^(5e))C(O)OR^(5b), —N(R^(5e))C(O)N(R^(5b))₂, or—N(R^(5e))SO₂N(R^(5b))₂, wherein R^(5b), R^(5c), R^(5dd), and R^(5e)have the values described herein.

In some embodiments, R^(5a) is halo, C₁₋₃alkyl, C₁₋₃haloalkyl,—O—C₁₋₃alkyl, —O—C₁₋₃ haloalkyl, —C(O)C₁₋₃ alkyl, —NHC(O)C₁₋₃alkyl,—NHC(O)NHC₁₋₃alkyl, or NHS(O)₂C₁₋₃ alkyl. In some embodiments, R^(5a) is—CH₂—R^(5dd), wherein R^(5dd) is phenyl, pyridyl, naphthyl or thienyloptionally substituted with 0-1 occurrence of R^(7a), wherein R^(7a) hasthe values described herein. In certain embodiments, R^(5a) is chloro,fluoro, methoxy, ethoxy, propoxy, isopropoxy, trifluoromethyl,trifluoromethoxy, methyl, ethyl, propyl, butyl, isopropyl, —NHC(O)CH₃,—NHC(O)CH₂CH₃, —NHC(O)NHCH₃, or —NHS(O)₂CH₃.

In some embodiments, each occurrence of R^(5a) is independently chloro,fluoro, C₁₋₄ alkyl, C₁₋₆ fluoroalkyl, —O—C₁₋₆ alkyl, —O—C₁₋₆fluoroalkyl, cyano, hydroxy, —NHC(O)C₁₋₆ alkyl, —NHC₁₋₆ alkyl,—N(C₁₋₆alkyl)₂, —C(O)NHC₁₋₆ alkyl, —C(O)N(C₁₋₆ alkyl)₂, —NHC(O)NHC₁₋₆alkyl, —NHC(O)N(C₁₋₆alkyl)₂, or —NHS(O)₂C₁₋₆ alkyl. In certainembodiments, each occurrence of R^(5a) is chloro, fluoro, methyl, ethyl,trifluoromethyl, methoxy, ethoxy, trifluoromethoxy, cyano, or hydroxy.

In some embodiments, each occurrence of R^(5b) is independently hydrogenor an optionally substituted group selected from C₁₋₆ aliphatic,3-10-membered cycloaliphatic, 4-10-membered heterocyclyl having 1-4heteroatoms independently selected from nitrogen, oxygen, and sulfur,6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatomsindependently selected from nitrogen, oxygen, and sulfur; or twooccurrences of R^(5b) on the same nitrogen atom can be taken togetherwith the nitrogen atom to which they are bound to form an optionallysubstituted 4-7-membered heterocyclyl ring having 0-1 additionalheteroatoms selected from nitrogen, oxygen, and sulfur.

In some embodiments, each occurrence of R^(5c) is independently anoptionally substituted group selected from C₁₋₆ aliphatic, 3-10-memberedcycloaliphatic, 4-10-membered heterocyclyl having 1-4 heteroatomsindependently selected from nitrogen, oxygen, and sulfur, 6-10-memberedaryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independentlyselected from nitrogen, oxygen, and sulfur.

In some embodiments, each occurrence of R^(5c) is independently hydrogenor an optionally substituted C₁₋₆ aliphatic group. In some otherembodiments, each occurrence of R^(5e) is independently hydrogen.

In some embodiments, the variable R⁶ is hydrogen, C₁₋₄ aliphatic, C₃₋₆cycloaliphatic, or 6-10-membered aryl. In some embodiments, R⁶ ishydrogen, C₁₋₄ aliphatic, or C₃₋₆ cycloaliphatic. In certainembodiments, R⁶ is hydrogen, methyl, ethyl, phenyl, cyclopropyl,cyclobutyl, or cyclopentyl. In certain embodiments, R⁶ is hydrogen ormethyl. In certain embodiments, R⁶ is hydrogen.

In some embodiments, the variable R^(6′) is hydrogen, C₁₋₄ aliphatic,C₃₋₆ cycloaliphatic, or 6-10-membered aryl. In some embodiments, R^(6′)is hydrogen, C₁₋₄ aliphatic, or C₃₋₆ cycloaliphatic. In certainembodiments, R^(6′) is hydrogen, methyl, ethyl, phenyl, cyclopropyl,cyclobutyl, or cyclopentyl. In certain embodiments, R^(6′) is hydrogenor methyl. In certain embodiments, R^(6′) is hydrogen.

In some embodiments, R⁶ and R^(6′) are taken together to form a C₃₋₆cycloaliphatic group. In certain embodiments, R⁶ and R^(6′) are takentogether to form a cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexylgroup.

In some embodiments, V_(2a) is —C(O)—, —O—, —S—, —N(R^(4a))—, or—C(O)N(R^(4a))—. In certain embodiments, V_(2a) is —NH— or —O—.

In some embodiments, V_(2a′) is —O—, —S—, or —N(R^(4a))—, wherein R^(4a)has the values described herein. In certain embodiments, V_(2a′) is —O—or —NH—.

In some embodiments, t is 2-3. In certain embodiments, t is 2. Incertain embodiments, t is 3.

In some embodiments, u is 2-3. In certain embodiments, u is 2. Incertain embodiments, u is 3.

In some embodiments, z is 0-3. In some embodiments, z is 0-1. In certainembodiments, z is 0. In certain embodiments, z is 1. In certainembodiments, z is 2. In certain embodiments, z is 3.

In some embodiments, y is 2-3. In certain embodiments, y is 2. Incertain embodiments, y is 3.

In some embodiments, V₃ is —N(R^(5e)), —O—, —S—, —S(O)—, —S(O)₂—,—C(O)—, —C(O)O—, C(O)N(R^(5e))—, —S(O)₂N(R^(5e))—, —OC(O)N(R^(5e))—,—N(R^(5e))C(O)—, —N(R^(5e))SO₂—, —N(R^(5e))C(O)O—,—N(R^(5e))C(O)N(R^(5e))—, —N(R^(5e))SO₂N(R^(5e))—, —OC(O)—, or—C(O)N(R^(5e))O—. In some embodiments, V₃ is —N(R^(5e)), —O—, —S—,—C(O)—, —C(O)O—, —C(O)N(R^(5e))—, or —S(O)₂N(R^(5e)). In someembodiments, V₃ is —NH—, —O—, —S—, or —C(O)—.

In some embodiments, L₃ is an optionally substituted C₁₋₃ alkylenechain, where one carbon atom may be replaced with —CR^(A)═CR^(A)—. Insome embodiments, L₃ is —CH₂—, CH₂CH₂—, —CH₂CH₂CH₂—, or —CH═CH—. In someembodiments, L₃ is —CH₂—. In some embodiments, L₃ is a C₁₋₃ alkylenechain, where one carbon atom may be replaced with —CR^(A)═CR^(A)—,optionally substituted with 0-2 occurrences of R^(8a), wherein eachoccurrence of R^(8a) is independently halogen, C₁₋₄ aliphatic, —CN,—NO₂, —N(R^(5b))₂, —OR^(5b), —SR^(5c), —S(O)₂R^(5c), —S(O)R^(5c),—C(O)R^(5b), —C(O)OR^(5b), —C(O)N(R^(5b))₂, —S(O)₂N(R^(5b))₂,—OC(O)N(R^(5b))₂, —N(R^(5e))C(O)R^(5b), —N(R^(5e))SO₂R^(5c),—N(R^(5e))C(O)OR^(5b), —N(R^(5e))C(O)N(R^(5b))₂, or—N(R^(5e))SO₂N(R^(5b))₂, or a C₁₋₄ aliphatic substituted with halogen,—CN, —NO₂, —N(R^(5b))₂, —OR^(5b), —SR^(5c), —S(O)₂R^(5c), —S(O)R^(5c),—C(O)R^(5b), —C(O)OR^(5b), —C(O)N(R^(5b))₂, —S(O)₂N(R^(5b))₂,—OC(O)N(R^(5b))², —N(R^(5e))C(O)R^(5b), —N(R^(5e))SO₂R^(5c),—N(R^(5e))C(O)OR^(5b), —N(R^(5e))C(O)N(R^(5b))₂, or—N(R^(5e))SO₂N(R^(5b))₂; or two occurrences of R^(5b) on the samenitrogen atom taken together with the nitrogen atom to which they arebound, form an optionally substituted 4-7-membered heterocyclyl ringhaving 0-1 additional heteroatoms selected from nitrogen, oxygen, andsulfur; wherein R^(5b), R^(5c) and R^(5e) have the values describedherein. In some embodiments, L₃ is a C₁₋₃ alkylene chain, where onecarbon atom may be replaced with —CR^(A)═CR^(A)—, optionally substitutedwith 0-2 occurrences of R^(8a), wherein each occurrence of R^(8a) isindependently fluoro or C₁₋₄ aliphatic.

In some embodiments, R^(5d) is an optionally substituted group selectedfrom 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5heteroatoms independently selected from nitrogen, oxygen, and sulfur. Insome embodiments, R^(5d) is an optionally substituted group selectedfrom 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5heteroatoms independently selected from nitrogen, oxygen, and sulfur,wherein R^(5d) if substituted, is substituted with 0-2 independentoccurrences of —R^(7a), wherein R^(7a) has the values described herein.In some embodiments, R^(5d) is an optionally substituted group selectedfrom 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5heteroatoms independently selected from nitrogen, oxygen, and sulfur,wherein R^(5d) if substituted is substituted with 0-1 independentoccurrences of R^(7a), wherein R^(7a) has the values described herein.

In some embodiments, R^(5d) is furanyl, thienyl, pyrrolyl, oxazolyl,thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl,triazolyl, thiadiazolyl, phenyl, naphthyl, pyranyl, pyridyl,pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, indolizipyl, indolyl,isoindolyl, indazolyl, benzimidazolyl, benzthiazolyl, benzothienyl,benzofuranyl, benzoxazolyl, benzo[c][1,2,5]oxadiazolyl,benzo[c][1,2,5]thiadiazolyl, benzo[d]oxazol-2(3H)-one,2,3-dihydrobenzo[b][1,4]dioxinyl, benzo[d][1,3]dioxolyl,2,3-dihydrobenzofuranyl, 4H-furo[3,2-b]pyrrolyl, purinyl, quinolyl,isoquinolyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, cinnolinyl,phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, or pteridinyl,wherein each of the foregoing groups is unsubstituted or substitutedwith 0-2 independent occurrences of —R^(7a), wherein R^(7a) has thevalues described herein. In certain embodiments, R^(5d) is thienyl,pyrrolyl, pyrazolyl, isoxazolyl, triazolyl, phenyl, pyridyl, orbenzothienyl, wherein each of the foregoing groups is unsubstituted orsubstituted with 0-1 occurrences of —R^(7a), wherein R^(7a) has thevalues described herein. In certain embodiments, R^(5d) is thienyl,pyrrolyl, pyrazolyl, isoxazolyl, triazolyl, phenyl, pyridyl,pyrimidinyl, or benzothienyl, wherein each of the foregoing groups isunsubstituted or substituted with 0-1 occurrences of —R^(7a), whereinR^(7a) has the values described herein.

In some embodiments, R^(5dd) is R^(5d). In some other embodiments,R^(5dd) is phenyl, pyridyl, naphthyl or thienyl, wherein each of theforegoing groups is unsubstituted or substituted with 0-1 occurrence ofR^(7a), wherein R^(7a) has the values described herein.

In some embodiments, R^(7a) is halo, C₁₋₃ alkyl, C₁₋₃haloalkyl, —O—C₁₋₃alkyl, —O—C₁₋₃ haloalkyl, —NHC(O)C₁₋₃ alkyl, —NHC(O)NHC₁₋₃ alkyl, orNHS(O)₂C₁₋₃ alkyl. In some embodiments, R^(7a) is chloro, fluoro,methoxy, ethoxy, propoxy, isopropoxy, trifluoromethyl, trifluoromethoxy,methyl, ethyl, propyl, isopropyl, —NHC(O)CH₃, —NHC(O)CH₂CH₃,—NHC(O)NHCH₃, or —NHS(O)₂CH₃. In some embodiments, each occurrence ofR^(7a) is chloro, fluoro, bromo, iodo, C₁₋₆ alkyl, C₁₋₆ fluoroalkyl,—O—C₁₋₆-fluoroalkyl, cyano, hydroxy, —NHC(O)C₁₋₆ alkyl, —NHC₁₋₆ alkyl,—N(C₁₋₆alkyl)₂, —C(O)NHC₁₋₆ alkyl, —C(O)N(C₁₋₆alkyl)₂, —NHC(O)NHC₁₋₆alkyl, —NHC(O)N(C₁₋₆ alkyl)₂, or —NHS(O)₂C₁₋₆ alkyl. In certainembodiments, R^(7a) is chloro, fluoro, methyl, ethyl, trifluoromethyl,methoxy, ethoxy, trifluoromethoxy, cyano, or hydroxy.

In certain embodiments:

G is —R³, —C(R⁶)(R^(6′))—R³, —C(O)—R³, or —S(O)₂—R³;

R⁶ is hydrogen, C₁₋₄ aliphatic, C₃₋₆ cycloaliphatic, or 6-10-memberedaryl;

R^(6′) is hydrogen, C₁₋₄ aliphatic, C₃₋₆ cycloaliphatic, or6-10-membered aryl; or

R⁶ and R^(6′) are taken together to form a C₃₋₆ cycloaliphatic group;

R³ is —R^(3a); and

R^(3a) is unsubstituted or substituted 6-10-membered aryl, orunsubstituted or substituted 5-10-membered heteroaryl having 1-5heteroatoms independently selected from nitrogen, oxygen, and sulfur;wherein R^(3a) if substituted is substituted with 0-1 occurrences of—R^(5a), and one occurrence of —R^(5d); wherein R^(5a) and R^(5d) havethe values described herein.

In certain embodiments:

G is —R³;

R³ is —R^(3b); and

R^(3b) is unsubstituted or substituted 6-10-membered aryl, orunsubstituted or substituted 5-10-membered heteroaryl having 1-5heteroatoms independently selected from nitrogen, oxygen, and sulfur;wherein R^(3b) if substituted is substituted with 0-2 independentoccurrences of —R^(5a);

wherein R^(5a) has the values described herein.

In certain embodiments:

G is —(CH₂)_(t)—R³ or —(CH₂)_(t)—V_(2a′)R³;

R³ is —R^(3c);

R^(3c) is unsubstituted or substituted 4-10-membered heterocyclyl having1-4 heteroatoms independently selected from nitrogen, oxygen, andsulfur, unsubstituted or substituted 6-10-membered aryl; orunsubstituted or substituted 5-10-membered heteroaryl having 1-4heteroatoms independently selected from nitrogen, oxygen, and sulfur,wherein R^(3c) if substituted is substituted with 0-2 independentoccurrences of —R^(5a);

V_(2a) is —C(O)—, —O—, —S—, —N(R^(4a))—, or —C(O)N(R^(4a))—; and

t is 2-3;

wherein R^(5a) and R^(4a) have the values described herein.

In certain embodiments:

G is —C(R⁶)(R^(6′))—R³, —C(O)—[C(R⁶)(R^(6′))]_(u)—R³,—S(O)₂—[C(R⁶)(R^(6′))]_(u)—R³, or —C(O)—NH—[C(R⁶)(R^(6′))]_(a)—R³;

R⁶ is hydrogen, C₁₋₄ aliphatic, C₃₋₆ cycloaliphatic, or 6-10-memberedaryl;

R^(6′) is hydrogen, C₁₋₄ aliphatic, C₃₋₆ cycloaliphatic, or6-10-membered aryl; or

R⁶ and R^(6′) are taken together to form a C₃₋₆ cycloaliphatic group;

R³ is —R^(3d);

R^(3d) is unsubstituted or substituted C₁₋₆ aliphatic, unsubstituted orsubstituted 3-10-membered cycloaliphatic, unsubstituted or substituted4-10-membered heterocyclyl having 1-4 heteroatoms independently selectedfrom nitrogen, oxygen, and sulfur, unsubstituted or substituted6-10-membered aryl, or unsubstituted or substituted 5-10-memberedheteroaryl having 1-5 heteroatoms independently selected from nitrogen,oxygen, and sulfur; wherein R^(3d) if substituted is substituted with0-2 independent occurrences of —R^(5a); and

u is 1-2;

wherein R^(5a) has the values described herein.

In certain embodiments, the compound of formula (I) is represented byformulas (II-A)-(II-B):

wherein:

each occurrence of R¹ is independently chloro, fluoro, methoxy, ethoxy,propoxy, cyano, trifluoromethyl, methyl, ethyl, n-propyl, isopropyl, ortert-butyl;

each occurrence of R² is independently chloro, fluoro, methoxy, ethoxy,propoxy, trifluoromethyl, methyl, ethyl, n-propyl, isopropyl, ortert-butyl;

n is 0-2;

R^(5a) is halo, C₁₋₃ alkyl, C₁₋₃haloalkyl, —O—C₁₋₃ alkyl, —O—C₁₋₃haloalkyl, —NHC(O)C₁₋₃ alkyl, —NHC(O)NHC₁₋₃ alkyl, or NHS(O)₂C₁₋₃ alkyl;

R^(5d) is optionally substituted with 0-2 occurrences of —R^(7a); and

each occurrence of R^(7a) is independently halo, C₁₋₃ alkyl,C₁₋₃haloalkyl, —O—C₁₋₃ alkyl, —O—C₁₋₃ haloalkyl, —NHC(O)C₁₋₃ alkyl,—NHC(O)NHC₁₋₃ alkyl, or NHS(O)₂C₁₋₃ alkyl;

wherein G has the values described herein.

In certain embodiments, the compound of formula (I) is represented byformula (II-C):

wherein:

each occurrence of R¹ is independently chloro, fluoro, methoxy, ethoxy,propoxy, cyano, trifluoromethyl, methyl, ethyl, n-propyl, isopropyl, ortert-butyl;

each occurrence of R² is independently chloro, fluoro, methoxy, ethoxy,propoxy, trifluoromethyl, methyl, ethyl, n-propyl, isopropyl, ortert-butyl;

n is 0-2;

R^(3d) is optionally substituted with 0-1 occurrences of —R^(5a); and

each occurrence of R^(5a) is independently halo, C₁₋₃ alkyl,C₁₋₃haloalkyl, —O—C₁₋₃ alkyl, —O—C₁₋₃ haloalkyl, —NHC(O)C₁₋₃alkyl,—NHC(O)NHC₁₋₃ alkyl, or NHS(O)₂C₁₋₃ alkyl;

wherein G has the values described herein.

In certain embodiments, the compound of formula (I) is represented byformula (II-A)-(II-C):

wherein:

G is —R³, —C(R⁶)(R^(6′))—R³, —C(O)—R³, or —S(O)₂—R³;

R⁶ is hydrogen, C₁₋₄ aliphatic, C₃₋₆ cycloaliphatic, or 6-10-memberedaryl;

R^(6′) is hydrogen, C₁₋₄ aliphatic, C₃₋₆ cycloaliphatic, or6-10-membered aryl; or

R⁶ and R^(6′) are taken together to form a C₃₋₆ cycloaliphatic group;

R³ is —R^(3a); and

R^(3a) is unsubstituted or substituted 6-10-membered aryl, orunsubstituted or substituted 5-10-membered heteroaryl having 1-5heteroatoms independently selected from nitrogen, oxygen, and sulfur,wherein R^(3a) if substituted is substituted with 0-1 occurrences of—R^(5a), and one occurrence of —R^(5d);

wherein R¹, R², R^(5a), R^(5d), and n have the values described herein.

In certain embodiments, described directly above:

R¹ is hydrogen, chloro, fluoro, methoxy, cyano, or methyl; eachoccurrence of R² is independently fluoro, methyl, or trifluoromethyl;

n is 0-2;

R^(5a) is chloro, fluoro, C₁₋₄ alkyl, C₁₋₆ fluoroalkyl, —O—C₁₋₆ alkyl,—O—C₁₋₆ fluoroalkyl, cyano, hydroxy, —NHC(O)C₁₋₆ alkyl, —NHC₁₋₆ alkyl,—N(C₁₋₆ alkyl)₂, —C(O)NHC₁₋₆ alkyl, —C(O)N(C₁₋₆alkyl)₂, —NHC(O)NHC₁₋₆alkyl, —NHC(O)N(C₁₋₆ alkyl)₂, or —NHS(O)₂C₁₋₆ alkyl;

R^(5d) if substituted is substituted with 0-2 occurrences of —R^(7a);and

each occurrence of R^(7a) is independently chloro, fluoro, bromo, iodo,C₁₋₆ alkyl, C₁₋₆ fluoroalkyl, —O—C₁₋₆ alkyl, —O—C₁₋₆ fluoroalkyl, cyano,hydroxy, —NHC(O)C₁₋₆ alkyl, —NHC₁₋₆ alkyl, —N(C₁₋₆ alkyl)₂, —C(O)NHC₁₋₆alkyl, —C(O)N(C₁₋₆ alkyl)₂, —NHC(O)NHC₁₋₆ alkyl, —NHC(O)N(C₁₋₆ alkyl)₂,or —NHS(O)₂C₁₋₆ alkyl;

wherein R^(5d) has the values described herein.

In certain embodiments, the compound of formula (I) is represented byformula (II-A)-(II-C):

wherein:

G is —[C(R⁶)(R^(6′))]_(z)—R³, —C(O)—[C(R⁶)(R^(6′))]_(z)—R³,—C(O)—NH—[C(R⁶)(R^(6′))]_(z)—R³, —S(O)₂—[C(R⁶)(R^(6′))]_(z)—R³,—[C(R⁶)(R^(6′))]_(y)—V_(2a)—R³, —C(O)—[C(R⁶)(R^(6′))]_(y)—V_(2a)—R³,—C(R⁶)(R^(6′))—V_(2a′)—R³, or —C(O)—C(R⁶)(R^(6′))—V_(2a′)—R³,

R⁶ is hydrogen, C₁₋₄ aliphatic, C₃₋₆ cycloaliphatic, or 6-10-memberedaryl;

R^(6′) is hydrogen, C₁₋₄ aliphatic, C₃₋₆ cycloaliphatic, or6-10-membered aryl; or

R⁶ and R^(6′) are taken together to form a C₃₋₆ cycloaliphatic group;

V_(2a) is —C(O)—, —O—, —S—, —N(R^(4a))—, or —C(O)N(R^(4a))—;

V_(2a′) is —O—, —S—, or —N(R^(4a))—;

R³ is —R^(3d);

R^(3d) is unsubstituted or substituted C₁₋₆ aliphatic, unsubstituted orsubstituted 3-10-membered cycloaliphatic, unsubstituted or substituted4-10-membered heterocyclyl having 1-4 heteroatoms independently selectedfrom nitrogen, oxygen, and sulfur, unsubstituted or substituted6-10-membered aryl, or unsubstituted or substituted 5-10-memberedheteroaryl having 1-5 heteroatoms independently selected from nitrogen,oxygen, and sulfur, wherein R^(3d) if substituted is substituted with0-2 independent occurrences of —R^(5a);

z is 0-3; and

y is 1-2;

wherein R¹, R², R^(5a), and n have the values described herein.

In certain embodiments, described directly above:

R¹ is hydrogen, chloro, fluoro, methoxy, cyano, or methyl; eachoccurrence of R² is independently fluoro, methyl, or trifluoromethyl;

n is 0-2;

R^(3d) is unsubstituted or substituted with 0-1 occurrences of —R^(5a);and

R^(5a) is chloro, fluoro, C₁₋₄ alkyl, C₁₋₆ fluoroalkyl, —O—C₁₋₆ alkyl,—O—C₁₋₆ fluoroalkyl, cyano, hydroxy, —NHC(O)C₁₋₆ alkyl, —NHC₁₋₆ alkyl,—N(C₁₋₆alkyl)₂, —C(O)NHC₁₋₆ alkyl, —C(O)N(C₁₋₆alkyl)₂, —NHC(O)NHC₁₋₆alkyl, —NHC(O)N(C₁₋₆alkyl)₂, or —NHS(O)₂C₁₋₆ alkyl;

wherein R^(5d) has the values described herein.

Representative examples of compounds of formula (I) are shown in Table1:

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

32

33

34

35

36

37

38

39

40

41

42

43

44

45

46

47

48

49

50

51

52

53

54

55

56

57

58

59

60

61

62

63

64

65

66

67

68

69

70

71

72

73

74

75

76

77

78

79

80

81

82

83

84

85

86

87

88

89

90

91

92

93

94

95

96

97

98

99

100

101

102

103

104

105

106

107

108

109

110

111

112

113

114

115

116

117

118

119

120

121

122

123

124

125

126

127

128

129

130

131

132

133

134

135

136

137

138

139

140

141

142

143

144

145

146

147

148

149

150

151

152

153

154

155

156

157

158

159

160

161

162

163

164

165

166

167

168

169

170

171

172

173

174

175

176

177

178

179

180

181

182

183

184

185

186

187

188

189

190

191

192

193

194

195

196

197

198

199

200

201

202

203

204

205

206

207

208

209

210

211

212

213

214

215

216

217

218

219

220

221

222

223

224

225

226

227

228

229

230

231

232

233

234

235

236

237

238

239

240

The compounds in Table 1 above may also be identified by the followingchemical names:

16-(2,2-dimethylpropanoyl)-N-hydroxy-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide26-(cyclohexylcarbonyl)-N-hydroxy-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide3N-hydroxy-6-[(1-methylcyclohexyl)carbonyl]-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide46-[2-(4-chlorophenyl)-2-methylpropanoyl]-N-hydroxy-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide 5N-hydroxy-6-(3-thienylcarbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide6N-hydroxy-6-(2-phenoxybutanoyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide76-[(5-chloro-4-methoxy-3-thienyl)carbonyl]-N-hydroxy-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide 8N-hydroxy-6-(4,5,6,7-tetrahydro-2H-indazol-3-ylcarbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide 96-(2,2-diphenylbutanoyl)-N-hydroxy-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide106-(dicyclohexylacetyl)-N-hydroxy-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide11N-hydroxy-6-{[2-methyl-4-(trifluoromethyl)-1,3-thiazol-5-yl]carbonyl}-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide 126-[(2,4-dimethylphenoxy)acetyl]-N-hydroxy-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide136-{[1-(2-chloro-4-fluorophenyl)cyclopentyl]carbonyl}-N-hydroxy-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide 146-[1-adamantylcarbonyl]-N-hydroxy-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide15N-hydroxy-6-{[1-(phenylsulfonyl)piperidin-2-yl]carbonyl}-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide 16N-hydroxy-6-[2-methyl-5-(piperidin-1-ylsulfonyl)-3-furoyl]-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide 176-(9H-fluoren-9-ylacetyl)-N-hydroxy-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide186-[(2,2-diphenylethyl)sulfonyl]-N-hydroxy-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide196-(butylsulfonyl)-N-hydroxy-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide206-[(3,5-dimethylisoxazol-4-yl)sulfonyl]-N-hydroxy-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide 21N-hydroxy-6-{[4-(trifluoromethyl)phenyl]sulfonyl}-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide 226-(3,4-dihydro-2H-1,5-benzodioxepin-7-ylmethyl)-N-hydroxy-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide 23N-hydroxy-6-[4-(1H-pyrazol-1-yl)benzyl]-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide24N-hydroxy-6-[(5-methyl-2-phenyl-2H-1,2,3-triazol-4-yl)methyl]-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide 256-(2,1,3-benzothiadiazol-4-ylmethyl)-N-hydroxy-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide265-(2,2-dimethylpropanoyl)-N-hydroxy-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxamide27N-hydroxy-5-[(1-methyl-1H-pyrrol-2-yl)carbonyl]-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxamide 28N-hydroxy-5-[(1-methylcyclohexyl)carbonyl]-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxamide29N-hydroxy-5-[(5-methylpyrazin-2-yl)carbonyl]-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxamide30N-hydroxy-5-(quinolin-8-ylcarbonyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxamide315-(cyclohexylcarbonyl)-N-hydroxy-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxamide325-[4-(4,6-dimethoxypyrimidin-2-yl)benzoyl]-N-hydroxy-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxamide 335-(1-adamantylcarbonyl)-N-hydroxy-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxamide34N-hydroxy-5-{[4-(trifluoromethyl)phenyl]sulfonyl}-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxamide 355-[3-(2,3-dihydro-1H-indol-1-yl)-3-oxopropyl]-N-hydroxy-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxamide 366-[3,5-bis(trifluoromethyl)benzoyl]-N-hydroxy-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide37N-hydroxy-5-[3-(trifluoromethoxy)benzyl]-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxamide38N-hydroxy-5-[(5-methoxy-1-methyl-1H-indol-2-yl)carbonyl]-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxamide 395-({5-[(cyclopropylcarbonyl)amino]-1-methyl-1H-indol-2-yl}carbonyl)-N-hydroxy-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxamide 40N²-hydroxy-N⁶-(5-phenyl-2-thienyl)-4,7-dihydrothieno[2,3-c]pyridine-2,6(5H)-dicarboxamide41N-hydroxy-6-{5-[4-(trifluoromethyl)phenyl]-1,3-thiazol-2-yl}-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide 426-(2-furoyl)-N-hydroxy-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide43N-hydroxy-5-{[5-(2-methoxyphenyl)-1,2,4-oxadiazol-3-yl]methyl}-3-methyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxamide 446-[2-(benzylamino)pyrimidin-4-yl]-N-hydroxy-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide45N⁵-[4-chloro-3-(trifluoromethyl)phenyl]-N²-hydroxy-6,7-dihydrothieno[3,2-c]pyridine-2,5(4H)-dicarboxamide 465-[5-(3-chlorophenyl)-1,3-thiazol-2-yl]-N-hydroxy-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxamide 476-[(2,4-dimethyl-1,3-thiazol-5-yl)acetyl]-N-hydroxy-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide 48N-hydroxy-6-[(2-methyl-4-phenylpyrimidin-5-yl)carbonyl]-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide 49N-hydroxy-4-methyl-6-[4-(trifluoromethyl)benzyl]-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide 50N-hydroxy-5-{5-[4-(trifluoromethyl)phenyl]-1,3-thiazol-2-yl}-5,6-dihydro-4H-thieno[2,3-c]pyrrole-2-carboxamide 516-(4-fluoro-3-methylbenzoyl)-N-hydroxy-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide526-[(3,5-difluorophenyl)acetyl]-N-hydroxy-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide53N-hydroxy-5-[5-(4-methoxyphenyl)-1,3-thiazol-2-yl]-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxamide 54N²-hydroxy-N⁶-[3-(trifluoromethyl)phenyl]-4,7-dihydrothieno[2,3-c]pyridine-2,6(5H)-dicarboxamide55N²-hydroxy-N⁵-(3-methoxybenzyl)-6,7-dihydrothieno[3,2-c]pyridine-2,5(4H)-dicarboxamide566-({3-[(2-amino-2-oxoethyl)sulfanyl]-2-thienyl}carbonyl)-N-hydroxy-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide 576-[2-(4-chlorophenoxy)ethyl]-N-hydroxy-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide586-({5-[(cyclopropylcarbonyl)amino]-1-methyl-1H-indol-2-yl}carbonyl)-N-hydroxy-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide 59N-hydroxy-6-(5-pyridin-4-yl-1,3-thiazol-2-yl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide60N⁵-(4-chlorobenzyl)-N²-hydroxy-6,7-dihydrothieno[3,2-c]pyridine-2,5(4H)-dicarboxamide61N⁵-[(1S)-1-(4-chlorophenyl)ethyl]-N²-hydroxy-6,7-dihydrothieno[3,2-c]pyridine-2,5(4H)-dicarboxamide626-[(3,5-dimethylisoxazol-4-yl)acetyl]-N-hydroxy-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide63N²-hydroxy-N⁶-(4-methoxybenzyl)-4,7-dihydrothieno[2,3-c]pyridine-2,6(5H)-dicarboxamide646-(4-tert-butylbenzoyl)-N-hydroxy-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide65N-hydroxy-6-[(5-methyl-2-phenyl-1,3-oxazol-4-yl)acetyl]-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide 665-{[2-(4-chloro-2-methoxyphenyl)-4-methyl-4H-furo[3,2-b]pyrrol-5-yl]carbonyl}-N-hydroxy-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxamide 676-(5-tert-butyl-2-methyl-3-furoyl)-N-hydroxy-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide68N-hydroxy-3-methyl-5-[4-(trifluoromethyl)benzyl]-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxamide 696-[(1-tert-butyl-3-methyl-1H-pyrazol-5-yl)carbonyl]-N-hydroxy-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide 70N-hydroxy-5-(quinolin-2-ylmethyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxamide716-[(4′-fluorobiphenyl-3-yl)sulfonyl]-N-hydroxy-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide726-[(1-cyclopropyl-1H-pyrrol-2-yl)carbonyl]-N-hydroxy-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide 73N-hydroxy-5-(5-pyridin-4-yl-1,3-thiazol-2-yl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxamide74N⁵-[2-fluoro-5-(trifluoromethyl)phenyl]-N²-hydroxy-6,7-dihydrothieno[3,2-c]pyridine-2,5(4H)-dicarboxamide 75N-hydroxy-6-[(2-methyl-1,3-thiazol-4-yl)acetyl]-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide76N⁶-cyclohexyl-N²-hydroxy-4,7-dihydrothieno[2,3-c]pyridine-2,6(5H)-dicarboxamide77N-hydroxy-6-[3-(trifluoromethoxy)benzyl]-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide785-[(1-cyclopropyl-1H-pyrrol-2-yl)carbonyl]-N-hydroxy-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxamide 79N²-hydroxy-N⁶-(3-methoxybenzyl)-4,7-dihydrothieno[2,3-c]pyridine-2,6(5H)-dicarboxamide80N²-hydroxy-N⁶-(3-methylphenyl)-4,7-dihydrothieno[2,3-c]pyridine-2,6(5H)-dicarboxamide81N-hydroxy-6-[(6-hydroxypyridin-2-yl)carbonyl]-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide825-[(4,5-dichloro-1-methyl-1H-pyrrol-2-yl)carbonyl]-N-hydroxy-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxamide 835-[(4-tert-butylphenyl)sulfonyl]-N-hydroxy-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxamide84N-hydroxy-6-[(5-methyl-1-phenyl-1H-pyrazol-4-yl)carbonyl]-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide 85N-hydroxy-6-(propylsulfonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide86N⁶-[2-fluoro-4-(trifluoromethyl)phenyl]-N²-hydroxy-4-methyl-4,7-dihydrothieno[2,3-c]pyridine-2,6(5H)-dicarboxamide 876-[2-(4-chlorophenoxy)ethyl]-N-hydroxy-7-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide 886-[(3-tert-butyl-1-methyl-1H-pyrazol-5-yl)carbonyl]-N-hydroxy-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide 89N-hydroxy-6-({[3-(trifluoromethyl)phenyl]sulfanyl}acetyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide 90N¹⁰-[4-chloro-3-(trifluoromethyl)phenyl]-N²-hydroxy-4,5,6,7,8,9-hexahydro-4,8-epiminocycloocta[b]thiophene-2,10-dicarboxamide 91N-hydroxy-6-(quinolin-2-ylmethyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide9210-[(1-cyclopropyl-1H-pyrrol-2-yl)carbonyl]-N-hydroxy-4,5,6,7,8,9-hexahydro-4,8-epiminocycloocta[b]thiophene-2-carboxamide 93N-hydroxy-6-{[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl}-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide 94N-hydroxy-6-(3-methyl-2-furoyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide95N-hydroxy-6-(quinolin-6-ylcarbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide96N-hydroxy-5-({5-[3-(trifluoromethyl)phenyl]-3-thienyl}sulfonyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxamide 975-[(4-tert-butylphenyl)sulfonyl]-N-hydroxy-7,7-dimethyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxamide 98N-hydroxy-6-[(4-methyl-1,3-thiazol-5-yl)carbonyl]-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide 99N-hydroxy-6-(quinolin-8-ylcarbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide1006-[(4,6-dimethoxypyrimidin-2-yl)carbonyl]-N-hydroxy-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide 101N-hydroxy-5-[5-(3-methyl-1-benzothien-2-yl)-1,3-thiazol-2-yl]-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxamide 102N-hydroxy-6-({5-[3-(trifluoromethyl)phenyl]-3-thienyl}sulfonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide 103N²-hydroxy-N⁶-(4-methylbenzyl)-4,7-dihydrothieno[2,3-c]pyridine-2,6(5H)-dicarboxamide10410-[2-(4-chlorophenoxy)ethyl]-N-hydroxy-4,5,6,7,8,9-hexahydro-4,8-epiminocycloocta[b]thiophene-2-carboxamide 105N-hydroxy-5-[4-(trifluoromethyl)benzyl]-5,6-dihydro-4H-thieno[2,3-c]pyrrole-2-carboxamide106N⁶-[2-fluoro-5-(trifluoromethyl)phenyl]-N²-hydroxy-4,7-dihydrothieno[2,3-c]pyridine-2,6(5H)-dicarboxamide 107N-hydroxy-6-[(5-methyl-3-phenylisoxazol-4-yl)carbonyl]-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide 1086-[(3-chloro-1-methyl-1H-indol-2-yl)carbonyl]-N-hydroxy-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide 109N²-hydroxy-N⁵-(4-methoxybenzyl)-6,7-dihydrothieno[3,2-c]pyridine-2,5(4H)-dicarboxamide1106-[5-(3-chlorophenyl)-1,3-thiazol-2-yl]-N-hydroxy-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide 111N-hydroxy-6-(4-methoxybenzyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide1126-{[2-(4-tert-butylphenyl)-4-methyl-4H-furo[3,2-b]pyrrol-5-yl]carbonyl}-N-hydroxy-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide 1135-[2-(benzylamino)pyrimidin-4-yl]-N-hydroxy-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxamide1146-{[2-(4-chloro-2-methoxyphenyl)-4-methyl-4H-furo[3,2-b]pyrrol-5-yl]carbonyl}-N-hydroxy-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide 1155-{[2-(5-cyano-2-thienyl)-4-methyl-4H-furo[3,2-b]pyrrol-5-yl]carbonyl}-N-hydroxy-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxamide 116N-hydroxy-6-[(1-methyl-1H-pyrrol-2-yl)carbonyl]-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide 117N⁶-[4-chloro-3-(trifluoromethyl)phenyl]-N²-hydroxy-4,7-dihydrothieno[2,3-c]pyridine-2,6(5H)-dicarboxamide 1186-[(4-tert-butylphenyl)acetyl]-N-hydroxy-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide119N-hydroxy-7,7-dimethyl-5-(quinolin-2-ylmethyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxamide120N-hydroxy-6-[(4′-methoxybiphenyl-4-yl)sulfonyl]-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide 1216-[(4-tert-butylphenyl)sulfonyl]-7-(2-fluorophenyl)-N-hydroxy-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide 1226-[3-(2,3-dihydro-1H-indol-1-yl)-3-oxopropyl]-N-hydroxy-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide 1236-{[2-(5-cyano-2-thienyl)-4-methyl-4H-furo[3,2-b]pyrrol-5-yl]carbonyl}-N-hydroxy-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide 1245-[(4′-fluorobiphenyl-3-yl)sulfonyl]-N-hydroxy-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxamide1256-[(3,5-dimethyl-1H-pyrazol-1-yl)acetyl]-N-hydroxy-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide 126N-hydroxy-5-{5-[4-(trifluoromethyl)phenyl]-1,3-thiazol-2-yl}-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxamide 127N-hydroxy-6-[(1-phenyl-1H-pyrazol-4-yl)carbonyl]-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide 1286-[(1-cyclopropyl-1H-pyrrol-2-yl)carbonyl]-7-(2-fluorophenyl)-N-hydroxy-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide 129N-hydroxy-5-{[5-(2-methoxyphenyl)-1,2,4-oxadiazol-3-yl]methyl}-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxamide 130N-hydroxy-6-{[5-(2-methoxyphenyl)-1,2,4-oxadiazol-3-yl]methyl}-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide 1316-[3,5-bis(acetylamino)benzoyl]-N-hydroxy-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide132N²-hydroxy-N⁶-(5-methyl-3-phenylisoxazol-4-yl)-4,7-dihydrothieno[2,3-c]pyridine-2,6(5H)-dicarboxamide 133N-hydroxy-6-[3-(1H-pyrazol-1-yl)benzoyl]-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide1346-[3-(2,3-dihydro-1H-indol-1-yl)-3-oxopropyl]-N-hydroxy-7-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide 135N-hydroxy-5-(propylsulfonyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxamide1366-[4-(benzylamino)pyrimidin-2-yl]-N-hydroxy-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide137N⁶-[(1S)-1-(4-chlorophenyl)ethyl]-N²-hydroxy-4,7-dihydrothieno[2,3-c]pyridine-2,6(5H)-dicarboxamide138N-hydroxy-7-methyl-6-{5-[4-(trifluoromethyl)phenyl]-1,3-thiazol-2-yl}-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide 139N²-hydroxy-N⁶-(4-isopropylphenyl)-4,7-dihydrothieno[2,3-c]pyridine-2,6(5H)-dicarboxamide1406-(3,5-difluorobenzoyl)-N-hydroxy-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide1415-(2,2-dimethylpropanoyl)-N-hydroxy-5,6-dihydro-4H-thieno[2,3-c]pyrrole-2-carboxamide1425-{[2-(4-tert-butylphenyl)-4-methyl-4H-furo[3,2-b]pyrrol-5-yl]carbonyl}-N-hydroxy-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxamide 1437-(2-fluorophenyl)-N-hydroxy-6-[3-(trifluoromethoxy)benzyl]-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide 144N-hydroxy-6-[5-(4-methoxyphenyl)-1,3-thiazol-2-yl]-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide 145N-hydroxy-5-({4-methyl-2-[3-(trifluoromethyl)phenyl]-4H-furo[3,2-b]pyrrol-5-yl}carbonyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxamide 146N-hydroxy-6-(1,3-thiazol-4-ylcarbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide147N⁶-[(1R)-1-(4-chlorophenyl)ethyl]-N²-hydroxy-4,7-dihydrothieno[2,3-c]pyridine-2,6(5H)-dicarboxamide1485-[(4,5-dichloro-1-methyl-1H-pyrrol-2-yl)carbonyl]-N-hydroxy-5,6-dihydro-4H-thieno[2,3-c]pyrrole-2-carboxamide 1496-[(1-ethyl-3-methyl-1H-pyrazol-5-yl)carbonyl]-N-hydroxy-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide 1505-[2-(4-chlorophenoxy)ethyl]-N-hydroxy-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxamide151N-hydroxy-5-[(4′-methoxybiphenyl-4-yl)sulfonyl]-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxamide 152N-hydroxy-6-[(4-methyl-2-phenylpyrimidin-5-yl)carbonyl]-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide 153N-hydroxy-3-methyl-5-(propylsulfonyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxamide154N⁵-[(1R)-1-(4-chlorophenyl)ethyl]-N²-hydroxy-6,7-dihydrothieno[3,2-c]pyridine-2,5(4H)-dicarboxamide155N⁶-(4-chlorobenzyl)-N²-hydroxy-4,7-dihydrothieno[2,3-c]pyridine-2,6(5H)-dicarboxamide156N-hydroxy-6-(2,3,5,6-tetrafluorobenzoyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide1575-[4-(benzylamino)pyrimidin-2-yl]-N-hydroxy-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxamide158N-hydroxy-6-[(5-methoxy-1-methyl-1H-indol-2-yl)carbonyl]-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide 1596-[(5-amino-1H-pyrazol-4-yl)carbonyl]-N-hydroxy-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide 1606-[(4-tert-butylphenyl)sulfonyl]-N-hydroxy-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide1615-[2-(4-chlorophenoxy)ethyl]-N-hydroxy-5,6-dihydro-4H-thieno[2,3-c]pyrrole-2-carboxamide162N-hydroxy-7,7-dimethyl-5-({4-methyl-2-[3-(trifluoromethyl)phenyl]-4H-furo[3,2-b]pyrrol-5-yl}carbonyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxamide 163N²-hydroxy-N⁶-(4-iodophenyl)-4,7-dihydrothieno[2,3-c]pyridine-2,6(5H)-dicarboxamide1646-[3-fluoro-5-(trifluoromethyl)benzoyl]-N-hydroxy-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide 165N-hydroxy-5-[4-(trifluoromethyl)benzyl]-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxamide166N-hydroxy-5-[(3-methoxy-1-methyl-1H-pyrrol-2-yl)carbonyl]-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxamide 167N-hydroxy-6-[5-(3-methyl-1-benzothien-2-yl)-1,3-thiazol-2-yl]-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide 1685-[(3-chloro-1-methyl-1H-indol-2-yl)carbonyl]-N-hydroxy-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxamide 169N⁶-(4-butylphenyl)-N²-hydroxy-4,7-dihydrothieno[2,3-c]pyridine-2,6(5H)-dicarboxamide1705-[(3-chloro-1-methyl-1H-indol-2-yl)carbonyl]-N-hydroxy-5,6-dihydro-4H-thieno[2,3-c]pyrrole-2-carboxamide 171N-hydroxy-6-[4-(trifluoromethyl)benzoyl]-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide172N-hydroxy-5-(propylsulfonyl)-5,6-dihydro-4H-thieno[2,3-c]pyrrole-2-carboxamide173 tert-butyl2-[(hydroxyamino)carbonyl]-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-carboxylate174N-hydroxy-6-[(3-methoxy-1-methyl-1H-pyrrol-2-yl)carbonyl]-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide 175N-hydroxy-6-[(5-methoxy-1-methyl-1H-indol-2-yl)carbonyl]-4-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide 176N²-hydroxy-N⁶-mesityl-4,7-dihydrothieno[2,3-c]pyridine-2,6(5H)-dicarboxamide1776-[(3,5-dimethylisoxazol-4-yl)carbonyl]-N-hydroxy-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide 1786-(2,5-dimethyl-3-furoyl)-N-hydroxy-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide179N-hydroxy-6-(quinolin-2-ylcarbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide180N-hydroxy-6-({4-methyl-2-[3-(trifluoromethyl)phenyl]-4H-furo[3,2-b]pyrrol-5-yl}carbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide 181N-hydroxy-6-[4-(trifluoromethyl)benzyl]-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide1826-(4-fluorobenzoyl)-N-hydroxy-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide1836-[(4,5-dichloro-1-methyl-1H-pyrrol-2-yl)carbonyl]-N-hydroxy-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide 1846-{[3-(4-fluorophenyl)-5-methylisoxazol-4-yl]carbonyl}-N-hydroxy-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide 185N-hydroxy-6-{[4-(trifluoromethyl)phenyl]acetyl}-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide 1866-[(3-ethyl-1-methyl-1H-pyrazol-5-yl)carbonyl]-N-hydroxy-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide 187N-hydroxy-6-[(5-methyl-1-phenyl-1H-pyrazol-4-yl)carbonyl]-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide 1886-[(4-tert-butylphenyl)acetyl]-N-hydroxy-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide189N⁵-(2,6-difluorophenyl)-N2-hydroxy-7,7-dimethyl-6,7-dihydrothieno[3,2-c]pyridine-2,5(4H)-dicarboxamide 1905-(4-tert-butylbenzoyl)-N-hydroxy-7,7-dimethyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxamide191N⁵-benzyl-N2-hydroxy-7,7-dimethyl-6,7-dihydrothieno[3,2-c]pyridine-2,5(4H)-dicarboxamide1925-[(3-chloro-1-benzothien-2-yl)carbonyl]-N-hydroxy-7,7-dimethyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxamide 1935-(4-chlorobenzoyl)-N-hydroxy-3-methyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxamide194N-hydroxy-3-methyl-5-[(1-methyl-1H-pyrrol-2-yl)carbonyl]-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxamide 1955-(1-benzothien-2-ylcarbonyl)-N-hydroxy-7,7-dimethyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxamide 196N⁵-(4-cyanophenyl)-N2-hydroxy-7,7-dimethyl-6,7-dihydrothieno[3,2-c]pyridine-2,5(4H)-dicarboxamide197N-hydroxy-3-methyl-5-[(2-methyl-1,3-thiazol-4-yl)carbonyl]-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxamide 1985-(3,4-dihydro-2H-1,5-benzodioxepin-7-ylcarbonyl)-N-hydroxy-7,7-dimethyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxamide 199N-hydroxy-3-methyl-5-[(4-methyl-2-pyridin-2-yl-1,3-thiazol-5-yl)carbonyl]-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxamide 200N⁵-(3,4-dimethylphenyl)-N2-hydroxy-7,7-dimethyl-6,7-dihydrothieno[3,2-c]pyridine-2,5(4H)-dicarboxamide 201N²-hydroxy-7,7-dimethyl-N5-[(1S)-1-phenylethyl]-6,7-dihydrothieno[3,2-c]pyridine-2,5(4H)-dicarboxamide 202N²-hydroxy-7,7-dimethyl-N5-[(1S)-1-phenylethyl]-6,7-dihydrothieno[3,2-c]pyridine-2,5(4H)-dicarboxamide 2035-[(3S,5S,7S)-1-adamantylcarbonyl]-N-hydroxy-3-methyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxamide 2045-(2,2-dimethylpropanoyl)-N-hydroxy-3-methyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxamide2055-(1-benzothien-2-ylcarbonyl)-N-hydroxy-3-methyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxamide 206N⁵-(2,3-dihydro-1-benzofuran-5-yl)-N²-hydroxy-7,7-dimethyl-6,7-dihydrothieno[3,2-c]pyridine-2,5(4H)-dicarboxamide 2075-(biphenyl-4-ylcarbonyl)-N-hydroxy-7,7-dimethyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxamide 208N-hydroxy-7,7-dimethyl-5-[(3-phenyl-1H-indol-2-yl)carbonyl]-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxamide 209N-hydroxy-5-(4-methoxybenzoyl)-3-methyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxamide210N-hydroxy-7,7-dimethyl-5-[(1-methyl-1H-pyrrol-2-yl)carbonyl]-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxamide 211N-hydroxy-7,7-dimethyl-5-[(5-pyridin-2-yl-2-thienyl)carbonyl]-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxamide 212 tert-butyl2-[(hydroxyamino)carbonyl]-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-carboxylate213N²-hydroxy-7,7-dimethyl-N⁵-(2-phenylethyl)-6,7-dihydrothieno[3,2-c]pyridine-2,5(4H)-dicarboxamide214N-hydroxy-5-(4-methoxybenzoyl)-7,7-dimethyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxamide2155-(1-benzofuran-2-ylcarbonyl)-N-hydroxy-7,7-dimethyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxamide 2165-(1-benzofuran-2-ylcarbonyl)-N-hydroxy-3-methyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxamide 217N-hydroxy-3-methyl-5-(pyridin-2-ylcarbonyl)-4,5,6,7-tetrahydrothieno[3,2,c]pyridine-2-carboxamide2185-(4-chlorobenzoyl)-N-hydroxy-7,7-dimethyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxamide219N-hydroxy-3-methyl-5-(phenylacetyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxamide220N-hydroxy-7,7-dimethyl-5-(pyridin-2-ylcarbonyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxamide 2215-[(3-chloro-1-benzothien-2-yl)carbonyl]-N-hydroxy-3-methyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxamide 222N-hydroxy-7,7-dimethyl-5-[(2-methyl-1,3-thiazol-4-yl)carbonyl]-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxamide 2235-(2,2-dimethylpropanoyl)-N-hydroxy-5,6-dihydro-4H-thieno[2,3-c]pyrrole-2-carboxamide224N-hydroxy-7,7-dimethyl-5-[(1-methylcyclohexyl)carbonyl]-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxamide 2255-(4-tert-butylbenzoyl)-N-hydroxy-3-methyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxamide226N-hydroxy-7,7-dimethyl-5-(2-thienylcarbonyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxamide227N-hydroxy-7,7-dimethyl-5-(phenylacetyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxamide228N-hydroxy-7,7-dimethyl-5-[(4-methyl-2-pyridin-2-yl-1,3-thiazol-5-yl)carbonyl]-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxamide 2295-butyryl-N-hydroxy-3-methyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxamide2305-(1-adamantylcarbonyl)-N-hydroxy-5,6-dihydro-4H-thieno[2,3-c]pyrrole-2-carboxamide2315-(1-benzothien-2-ylcarbonyl)-N-hydroxy-5,6-dihydro-4H-thieno[2,3-c]pyrrole-2-carboxamide232N-hydroxy-3-methyl-5-[(1-methylcyclohexyl)carbonyl]-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxamide 2335-(biphenyl-4-ylcarbonyl)-N-hydroxy-3-methyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxamide2345-(2-chlorobenzoyl)-N-hydroxy-7,7-dimethyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxamide235N-hydroxy-6-(pyridin-3-ylmethyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide236N⁵-[2-(dimethylamino)ethyl]-N²-hydroxy-7,7-dimethyl-6,7-dihydrothieno[3,2-c]pyridine-2,5(4H)-dicarboxamide 237N-hydroxy-3-methyl-5-[(4-methylpiperidin-4-yl)carbonyl]-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxamide 238N-hydroxy-6-(piperidin-4-ylcarbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide239N-hydroxy-5-[(2S)-3-methyl-2-(methylamino)butanoyl]-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxamide4. General Synthetic Methods and Intermediates

The compounds of the present invention can be prepared by methods knownto one of ordinary skill in the art and/or by reference to the schemesshown below and the synthetic examples that follow. Exemplary syntheticroutes are set forth in Schemes below, and in the Examples.

One of ordinary skill in the art will appreciate that thetransformations shown below in Schemes can also be carried out onanalogous compounds containing one or more substitutents on Ring A andat the R¹ position, or on analogous compounds with different Ring A ringsizes.

Scheme 1 shows a general route for preparing compounds of formula iii.As shown in Scheme 1, methyl4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxylate i, is treated witha carboxylic acid, R³—CO₂H, using a coupling agent in the presence of abase (Method A). Suitable coupling agents include, but are not limitedto, 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate (HBTU), orO-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate (HATU). Suitable bases for Method A include, but arenot limited to, triethylamine, N,N′-diisopropylethylamine andN-methylmorpholine. Suitable solvents for Method A include, but are notlimited to, dichloromethane (DCM), tetrahydrofuran (THF),N,N′-dimethylformamide (DMF), N-methylpyrrolidone (NMP) orN,N′-dimethylacetamide. Conversion of ii to the correspondinghydroxamate iii is achieved by heating ii in the presence ofhydroxylamine hydrochloride and potassium hydroxide in an appropriatesolvent such as methanol (Method B). Conversion to the correspondinghydroxamate can also be achieved using the potassium salt ofhydroxylamine (Huang et al., J. Med. Chem. 2009, 52(21):675).

Scheme 2 shows a general route for preparing compounds of formula vi.Amides of formula iv, where v is 1-2, are prepared by Method A, usingeither chloroacetic acid or 3-chloropropionic acid, and are then reactedwith oxygen (R³—OH) or nitrogen nucleophiles (R³—NH₂) in a solvent suchas CH₂Cl₂ or DMF, in the presence of a base, such asN,N′-diisopropylethylamine (Method C; see Takikawa et al., Organic Lett.2007, 9(14):2713-2716; Slee et al., J. Med. Chem. 2008, 51(6):1730-1739)to give compounds of formula vi where X is —O— or —NH—. Subsequentconversion of compounds of formula v to the corresponding hydroxamatesvi is carried out as described in Scheme 1 using Method B.

Scheme 3 shows a general route for preparing compounds of formula viii.As shown in Scheme 3, methyl4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxylate i is treated withthe appropriate sulfonyl chloride, R³—SO₂Cl, and DMAP in DMF at ambienttemperature (Method D). Method D may also be carried out in a solventsuch as DCM or N,N′-dimethylacetamide. Subsequent conversion of theresulting compounds of formula vii to the corresponding hydroxamatesviii is carried out as described in Scheme 1 using Method B.

Scheme 4 shows a general route for preparing compounds of formula xi.Sulfonamides of formula ix bearing a pendant aromatic bromide can beprepared as described in Scheme 3, and are then subjected to a Suzukicoupling with a boronic acid, R^(5d′)—B(OH)₂, in the presence of aPd-catalyst such as Pd(PPh₃)₄, and a base such as Na₂CO₃ (see Weinsteinet al., Bioorg. Med. Chem. Lett. 2005 15(5): 1435-1440) to affordsulfonamides of formula x. Other Pd-mediated coupling conditions such asthe reaction of an organo-stannane compound with an aromatic halide, orreaction with amines in a Buchwald-Hartiwig type coupling may beemployed to generate compounds of formula x where R^(5d′) is for examplean aromatic ring, a heteroaromatic ring or an amine containing moiety.Subsequent conversion of compounds of formula x to the correspondinghydroxamates of formula xi is carried out as described in Scheme 1 usingMethod B.

Scheme 5 shows a general route for preparing compounds of formula xiii.As shown in Scheme 5, methyl4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxylate i is treated withan appropriate alkyl halide (R³—CH₂—Br or R³—CH₂—Cl), in the presence ofa suitable base such as Et₃N in a solvent such as DMF (Method F) toafford compounds of formula xii. Alternatively, a reductive alkylationwith an aldehyde in the presence of a reducing agent can be used togenerate compounds of formula xii. Subsequent conversion of compounds offormula xii to the corresponding hydroxamate xiii is carried out asdescribed in Scheme 1 (Method B).

Scheme 6 shows a general route for preparing compounds of formula xv. Asshown in Scheme 6, a solution of methyl4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxylate i, and optionallya base in a solvent is treated with an isocyanate (R³—NCO), at ambientor elevated temperature to afford compounds of formula xiv (Method G).Suitable bases for Method G include, but are not limited totriethylamine, N,N′-diisopropylethylamine and N-methylmorpholine.Suitable solvents for Method G include, but are not limited to, DCM,THF, DMF, NMP and N,N′-dimethylacetamide. Subsequent conversion ofcompounds of formula xiv to the corresponding hydroxamates of formula xvis carried out as described in Scheme 1 using Method B.

Scheme 7 shows a general route for preparing compounds of formula xviiiAs shown in Scheme 7, methyl4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxylate i is treated withammonium thiocyanate in a solvent such as THF at an elevated temperature(Method H). Cyclization of the resulting thiourea xvi to theaminothiazole xvii is accomplished upon treatment with analpha-haloketone, (for example; R⁵—C(O)—CH₂Cl) in a solvent such as1,4-dioxane at ambient or elevated temperature (Method I). Subsequentconversion of compounds of formula xvii to the correspondinghydroxamates of formula xviii is carried out as described in Scheme 1using Method B.

Scheme 8 shows a general route for preparing compounds of formula xxviand xxvii. Ring expansion of compound xix, (prepared as described byPadwa et. al., J. Org. Chem. 1989, 54(2): 299-308) via a Schmidtrearrangement (Method J) followed by reduction of the resulting amideswith borane (Method K) affords amines XX and xxi (in a fashion analogousto that described in PCT Int. Appl. Pub. WO 08/076,954). Subsequentprotection of the amines with Boc-anhydride provides compounds xxii andxxiii (Method L). Bromination of xxii and xxiii followed by Pd-catalyzedcarbonylation with carbon monoxide provides intermediates xxiv and xxv(Method M; as exemplified in Janetka et al., Bioorg. Med. Chem. Lett.2008, 18(14): 4242-4248; and PCT Int. Appl. Pub. WO 05/037214).Subsequent removal of the Boc-protecting group (Method N) under acidicconditions yields compounds xxvi and xxvii. It will be appreciated thatanalogous transformations to those described in Scheme 1-7 above can beachieved starting from the compounds formula xxvi and xxvii.

Scheme 9 shows a general route for the preparation of compounds offormula xxxiii from commercially available halo-pyridines. Reaction ofpyridine xxviii with LDA followed by quenching with DMF gives pyridinealdehyde xxix (Method O, see Ondi et al., Tetrahedron 2005, 61(3),717-725). Palladium catalyzed reaction of xxix with Ar-boronic acids orAr-boronates (where Ar is substituted or unsubstituted aryl orheteroaryl) affords compounds of formula XXX (Method P, see Fujihara etal., Organic Letters 2009, 11(10): 2121-2124; Rocca et al., J. Org.Chem. 1993, 58(27): 7831; and Rocca et al., Tetrahedron 1993, 49(1):49). Treatment with methyl 2-mercaptoacetate affects cyclization to thecompound of formula xxxi (Method Q; see PCT Int. Appl. Pub. WO05/110410). The pyridine ring is reduced followed by de-methylation toyields compounds of formula xxxiii (Methods R, S). It will beappreciated that analogous transformations to those described in Schemes1-7 above can be achieved starting from the compounds of formula xxxiii.

Scheme 10 shows the methods described in Scheme 9 above applied togenerate substituted compounds of formulas xxxv and xxxvii starting fromcommercially available halo-pyridines xxxiv and xxxvi. It will beappreciated that analogous transformations to those described in Schemes1-7 above can be achieved starting from the compounds of formula xxxvand xxxvii.

Scheme 11 shows a general route for the preparation of compounds offormula xxxxii. Cyclocondensation of 1,5-dicarbonyl compounds of formulaxxxviii with ammonia, followed by dehydrogenation gives compounds offormula xxxix (Method T, see Kim et al., Tetrahedron Lett. 2008, 49(41):5863-5866). Nitration of the compound of formula xxxix affords thecompound of formula xxxx (Method U, see Katritzky et al., Organic &Biomolecular Chemistry 2005, 3(3): 538-541). Reduction of the nitrogroup followed by conversion of the aniline intermediate to fluorinegives compounds of formula xxxxi (Method V, see Motoyama et al., OrganicLetters 2009, 11(6): 1345-1348; Clark et al., Bioorg. Med. Chem. 2008,16(6): 3163-3170). Conversion of the compound of formula xxxxi tocompounds of formula xxxxii can be achieved with the methods describedabove (Methods O, Q, R, S). It will be appreciated that analogoustransformations to those described in Schemes 1-7 above can be achievedstarting from the compounds of formula xxxxii.

Scheme 12 above shows an extension of the chemistry described in Schemes9 and 11 to generate compounds of formula xxxxv. Bromination of pyridinexxxx with NBS gives compounds of formula xxxxiii (Method W, see Carrollet al., J. Med. Chem. 2002, 45(21): 4755-4761). The pyridine of formulaxxxxiii can be converted to compounds of formula xxxxiv by a palladiumcatalyzed coupling reaction in a similar manner as described in Scheme 9(Method P). The conversion of the compounds of formula xxxxiv to xxxxvcan be achieved as described above in Schemes 9 and 11 (Methods V, O. Q,R, S). It will be appreciated that analogous transformations to thosedescribed in Schemes 1-7 above can be achieved starting from thecompounds of formula xxxxv.

Scheme 13 shows another general route for the preparation of thecompound of formula xxxxviii. Condensation of ethylmercaptoacetate withcommercially available compound xxxxvi in the presence of base (MethodX, see Pessoa-Mahana et al. Heterocycles 2008, 75(8), 1913-1929; PCTInt. Appl. Pub. WO 05/110410) affords the compound of formula xxxxvii.Reduction of the pyridyl ring can be achieved using hydrogen over Adam'scatalyst (Method Y, see Wang et al., J. Med: Chem. 2007, 50, 199-210) togive compounds of formula xxxxviii. It will be appreciated thatanalogous transformations to those described in Schemes 1-7 above can beachieved starting from the compounds of formula xxxxviii.

Scheme 14 above shows a general route for the preparation of compoundsof formula Lii. Protected piperidones xxxxix (where each R² may be thesame or different; derived from commercial sources or accessed throughliterature routes) can be chloroformylated using a Vilsmer-Hack reactionto afford compounds of formula L (Method Z, see Grunewald et al.,Bioorg. Med. Chem. 2008, 16(1), 542-559). Treatment withethylmercaptoacetate in the presence of excess triethylamine providescompounds of formula Li (Method AA, see Venkatesan et al., J. Med. Chem.2006, 45(15), 4623). Subsequent removal of the Boc-protecting group(Method N) under acidic conditions yields compounds of formula Lii. Itwill be appreciated that analogous transformations to those described inSchemes 1-7 above can be achieved starting from the compounds of formulaLii.

Scheme 15 above shows a general route for the preparation of thecompound of formula Lv. Condensation of Liii (prepared as described byTucker et al., J. Med. Chem. 2008, 51(20), 6503-6511) withethylmercaptoacetate in the presence of a base affords the bicycliccompound of formula Liv (Method BB; see PCT Int. Appl. Pub. WO05/077926). The pyridyl ring can then be reduced with hydrogen overAdam's catalyst (Method Y). It will be appreciated that analogoustransformations to those described in Schemes 1-7 above can be achievedstarting from the compound of formula Lv.

Scheme 16 above shows a general route for the preparation of thecompound of formula Lx. Protection of the secondary amine of compoundxxxxviii can be achieved employing standard Boc anhydride in thepresence of a suitable base (Method L; see Wang et al., J. Med. Chem.2007, 50(2):199-210). Saponificiation of the ester of Lvi with sodiumhydroxide (Method CC) provides the free acid of compound Lvii whichassists in the ortho-metallation at C-3 with t-BuLi which, uponquenching with N-fluorobenzenesulfonimide, generates compound Lviii(Method DD, see Torrado et al., Bioorg. Med. Chem. 2004, 12(20):5277-5295). Re-esterfication is accomplished with TMS-diazomethane(Method EE) followed by removal of the Boc protecting group under acidicconditions (Method N) to generate compound Lx. It will be appreciatedthat analogous transformations to those described in Schemes 1-7 abovecan be achieved starting from the compound of formula Lx.

Scheme 17 above shows a general route for the preparation of thecompound of formula Lxiii. Starting from the compound of formula Lvii(prepared as described above in Scheme 16), the compound of formula Lxican be achieved through the carboxylic acid assisted ortho-metallationof Lvii with sec-BuLi/TMEDA followed by quenching with N-chlorosuccinimide (Method DD, see Torrado et al., Bioorg. Med. Chem. 2004,12(20): 5277-5295). Subsequent modification of the protecting groups isachieved though esterification with TMS-diazomethane (Method EE)followed by removal of the Boc group under acidic conditions (Method N)to provide the compound of formula Lxiii. It will be appreciated thatanalogous transformations to those described in Schemes 1-7 above can beachieved starting from the compound of formula Lxiii.

Scheme 18 above shows a general route for the preparation of thecompound of formula Lxvii. Condensation of commercially available Lxivwith ethylmercaptoacetate, followed by subsequent cyclization underbasic conditions provides the compound of formula Lxv (Method FF, seeU.S. App. Pub. No. 2006/0003990; Donoso et al. Synthesis 1992,(6):526-8). Methylation of the free hydroxyl, accomplished upontreatment with diazo((trimethylsilyl))methane (Method GG, see U.S. App.Pub. No. 2006/0003990) followed by removal of the Boc protecting groupunder acidic conditions (Method N) affords the compound of formulaLxvii. It will be appreciated that analogous transformations to thosedescribed in Schemes 1-7 above can be achieved starting from thecompound of formula Lxvii.

5. Uses, Formulation and Administration

As discussed above, the present invention provides compounds andpharmaceutical compositions that are useful as inhibitors of HDACenzymes, particularly HDAC6, and thus the present compounds are usefulfor treating proliferative, inflammatory, infectious, neurological orcardiovascular disorders.

In some embodiments, the invention provides the compound of formula (I),or a pharmaceutically acceptable salt thereof, for use in treating aproliferative disorder. In some embodiments, the invention provides apharmaceutical composition for the treatment of a proliferative disordercomprising the compound of formula (I), or a pharmaceutically acceptablesalt thereof. In some embodiments, the invention provides the use of thecompound of formula (I), or a pharmaceutically acceptable salt thereof,for the preparation of a pharmaceutical composition for the treatment ofa proliferative disorder. In some embodiments, the invention providesthe use of an effective amount of the compound of formula (I), or apharmaceutically acceptable salt thereof, for the treatment of aproliferative disorder.

The compounds and pharmaceutical compositions of the invention areparticularly useful for the treatment of cancer. As used herein, theterm “cancer” refers to a cellular disorder characterized byuncontrolled or disregulated cell proliferation, decreased cellulardifferentiation, inappropriate ability to invade surrounding tissue,and/or ability to establish new growth at ectopic sites. The term“cancer” includes, but is not limited to, solid tumors and bloodbornetumors. The term “cancer” encompasses diseases of skin, tissues, organs,bone, cartilage, blood, and vessels. The term “cancer” furtherencompasses primary and metastatic cancers.

Non-limiting examples of solid tumors that can be treated with thedisclosed inhibitors include pancreatic cancer; bladder cancer;colorectal cancer; breast cancer, including metastatic breast cancer;prostate cancer, including androgen-dependent and androgen-independentprostate cancer; renal cancer, including, e.g., metastatic renal cellcarcinoma; hepatocellular cancer; lung cancer, including, e.g.,non-small cell lung cancer (NSCLC), bronchioloalveolar carcinoma (BAC),and adenocarcinoma of the lung; ovarian cancer, including, e.g.,progressive epithelial or primary peritoneal cancer; cervical cancer;gastric cancer; esophageal cancer; head and neck cancer, including,e.g., squamous cell carcinoma of the head and neck; melanoma;neuroendocrine cancer, including metastatic neuroendocrine tumors; braintumors, including, e.g., glioma, anaplastic oligodendroglioma, adultglioblastoma multiforme, and adult anaplastic astrocytoma; bone cancer;and soft tissue sarcoma.

Non-limiting examples of hematologic malignancies that can be treatedwith the disclosed inhibitors include acute myeloid leukemia (AML);chronic myelogenous leukemia (CML), including accelerated CML and CMLblast phase (CML-BP); acute lymphoblastic leukemia (ALL); chroniclymphocytic leukemia (CLL); Hodgkin's disease (HD); non-Hodgkin'slymphoma (NHL), including follicular lymphoma and mantle cell lymphoma;B-cell lymphoma; T-cell lymphoma; multiple myeloma (MM); Waldenstrom'smacroglobulinemia; myelodysplastic syndromes (MDS), including refractoryanemia (RA), refractory anemia with ringed siderblasts (RARS),(refractory anemia with excess blasts (RAEB), and RAEB in transformation(RAEB-T); and myeloproliferative syndromes.

In some embodiments, compounds of the invention are suitable for thetreatment of breast cancer, lung cancer, ovarian cancer, multiplemyeloma, acute myeloid leukemia or acute lymphoblastic leukemia.

In other embodiments, compounds of the invention are suitable for thetreatment of inflammatory and cardiovascular disorders including, butnot limited to, allergies/anaphylaxis, acute and chronic inflammation,rheumatoid arthritis; autoimmunity disorders, thrombosis, hypertension,cardiac hypertrophy, and heart failure.

Accordingly, in another aspect of the present invention, pharmaceuticalcompositions are provided, wherein these compositions comprise any ofthe compounds as described herein, and optionally comprise apharmaceutically acceptable carrier, adjuvant or vehicle. In certainembodiments, these compositions optionally further comprise one or moreadditional therapeutic agents.

It will also be appreciated that certain of the compounds of presentinvention can exist in free form for treatment, or where appropriate, asa pharmaceutically acceptable derivative thereof. According to thepresent invention, a pharmaceutically acceptable derivative includes,but is not limited to, pharmaceutically acceptable prodrugs, salts,esters, salts of such esters, or any other adduct or derivative whichupon administration to a patient in need is capable of providing,directly or indirectly, a compound as otherwise described herein, or ametabolite or residue thereof.

As used herein, the term “pharmaceutically acceptable salt” refers tothose salts which are, within the scope of sound medical judgment,suitable for use in contact with the tissues of humans and lower animalswithout undue toxicity, irritation, allergic response and the like, andare commensurate with a reasonable benefit/risk ratio. A“pharmaceutically acceptable salt” means any non-toxic salt or salt ofan ester of a compound of this invention that, upon administration to arecipient, is capable of providing, either directly or indirectly, acompound of this invention or an inhibitorily active metabolite orresidue thereof. As used herein, the term “inhibitorily activemetabolite or residue thereof” means that a metabolite or residuethereof is also an inhibitor of HDAC6.

Pharmaceutically acceptable salts are well known in the art. Forexample, S. M. Berge et al., describe pharmaceutically acceptable saltsin detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, incorporatedherein by reference. Pharmaceutically acceptable salts of the compoundsof this invention include those derived from suitable inorganic andorganic acids and bases. Examples of pharmaceutically acceptable,nontoxic acid addition salts are salts of an amino group formed withinorganic acids such as hydrochloric acid, hydrobromic acid, phosphoricacid, sulfuric acid and perchloric acid or with organic acids such asacetic acid, oxalic acid, maleic acid, tartaric acid, citric acid,succinic acid or malonic acid or by using other methods used in the artsuch as ion exchange. Other pharmaceutically acceptable salts includeadipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate,bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate,cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate,formate, fumarate, glucoheptonate, glycerophosphate, gluconate,hemisulfate, heptanoate, hexanoate, hydroiodide,2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, laurylsulfate, malate, maleate, malonate, methanesulfonate,2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate,pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate,pivalate, propionate, stearate, succinate, sulfate, tartrate,thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and thelike. Salts derived from appropriate bases include alkali metal,alkaline earth metal, ammonium and N⁺(C₁₋₄alkyl)₄ salts. This inventionalso envisions the quaternization of any basic nitrogen-containinggroups of the compounds disclosed herein. Water or oil-soluble ordispersable products may be obtained by such quaternization.Representative alkali or alkaline earth metal salts include sodium,lithium, potassium, calcium, magnesium, and the like. Furtherpharmaceutically acceptable salts include, when appropriate, nontoxicammonium, quaternary ammonium, and amine cations formed usingcounterions such as halide, hydroxide, carboxylate, sulfate, phosphate,nitrate, loweralkyl sulfonate and aryl sulfonate.

As described above, the pharmaceutically acceptable compositions of thepresent invention additionally comprise a pharmaceutically acceptablecarrier, adjuvant, or vehicle, which, as used herein, includes any andall solvents, diluents, or other liquid vehicle, dispersion orsuspension aids, surface active agents, isotonic agents, thickening oremulsifying agents, preservatives, solid binders, lubricants and thelike, as suited to the particular dosage form desired. Remington'sPharmaceutical Sciences, Sixteenth Edition, E. W. Martin (MackPublishing Co., Easton, Pa., 1980) discloses various carriers used informulating pharmaceutically acceptable compositions and knowntechniques for the preparation thereof. Except insofar as anyconventional carrier medium is incompatible with the compounds of theinvention, such as by producing any undesirable biological effect orotherwise interacting in a deleterious manner with any othercomponent(s) of the pharmaceutically acceptable composition, its use iscontemplated to be within the scope of this invention. Some examples ofmaterials which can serve as pharmaceutically acceptable carriersinclude, but are not limited to, ion exchangers, alumina, aluminumstearate, lecithin, serum proteins, such as human serum albumin, buffersubstances such as phosphates, glycine, sorbic acid, or potassiumsorbate, partial glyceride mixtures of saturated vegetable fatty acids,water, salts or electrolytes, such as protamine sulfate, disodiumhydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zincsalts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone,polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, woolfat, sugars such as lactose, glucose and sucrose; starches such as cornstarch and potato starch; cellulose and its derivatives such as sodiumcarboxymethyl cellulose, ethyl cellulose and cellulose acetate; powderedtragacanth; malt; gelatin; talc; excipients such as cocoa butter andsuppository waxes; oils such as peanut oil, cottonseed oil; saffloweroil; sesame oil; olive oil; corn oil and soybean oil; glycols; such apropylene glycol or polyethylene glycol; esters such as ethyl oleate andethyl laurate; agar; buffering agents such as magnesium hydroxide andaluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline;Ringer's solution; ethyl alcohol, and phosphate buffer solutions, aswell as other non-toxic compatible lubricants such as sodium laurylsulfate and magnesium stearate, as well as coloring agents, releasingagents, coating agents, sweetening, flavoring and perfuming agents,preservatives and antioxidants can also be present in the composition,according to the judgment of the formulator.

In yet another aspect, a method for treating a proliferative,inflammatory, infectious, neurological or cardiovascular disorder isprovided comprising administering an effective amount of a compound, ora pharmaceutical composition to a subject in need thereof. In certainembodiments of the present invention an “effective amount” of thecompound or pharmaceutical composition is that amount effective fortreating a proliferative, inflammatory, infectious, neurological orcardiovascular disorder, or is that amount effective for treatingcancer. In other embodiments, an “effective amount” of a compound is anamount which inhibits binding of HDAC6, and thereby blocks the resultingsignaling cascades that lead to the abnormal activity of growth factors,receptor tyrosine kinases, protein serine/threonine kinases, G proteincoupled receptors and phospholipid kinases and phosphatases.

The compounds and compositions, according to the method of the presentinvention, may be administered using any amount and any route ofadministration effective for treating the disease. The exact amountrequired will vary from subject to subject, depending on the species,age, and general condition of the subject, the severity of theinfection, the particular agent, its mode of administration, and thelike. The compounds of the invention are preferably formulated in dosageunit form for ease of administration and uniformity of dosage. Theexpression “dosage unit form” as used herein refers to a physicallydiscrete unit of agent appropriate for the patient to be treated. Itwill be understood, however, that the total daily usage of the compoundsand compositions of the present invention will be decided by theattending physician within the scope of sound medical judgment. Thespecific effective dose level for any particular patient or organismwill depend upon a variety of factors including the disease beingtreated and the severity of the disease; the activity of the specificcompound employed; the specific composition employed; the age, bodyweight, general health, sex and diet of the patient; the time ofadministration, route of administration, and rate of excretion of thespecific compound employed; the duration of the treatment; drugs used incombination or coincidental with the specific compound employed, andlike factors well known in the medical arts. The term “patient”, as usedherein, means an animal, preferably a mammal, and most preferably ahuman.

The pharmaceutically acceptable compositions of this invention can beadministered to humans and other animals orally, rectally, parenterally,intracistemally, intravaginally, intraperitoneally, topically (as bypowders, ointments, or drops), bucally, as an oral or nasal spray, orthe like, depending on the severity of the infection being treated. Incertain embodiments, the compounds of the invention may be administeredorally or parenterally at dosage levels of about 0.01 mg/kg to about 50mg/kg and preferably from about 1 mg/kg to about 25 mg/kg, of subjectbody weight per day, one or more times a day, to obtain the desiredtherapeutic effect.

Liquid dosage forms for oral administration include, but are not limitedto, pharmaceutically acceptable emulsions, microemulsions, solutions,suspensions, syrups and elixirs. In addition to the active compounds,the liquid dosage forms may contain inert diluents commonly used in theart such as, for example, water or other solvents, solubilizing agentsand emulsifiers such as ethyl alcohol, isopropyl alcohol, ethylcarbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propyleneglycol, 1,3-butylene glycol, dimethylformamide, oils (in particular,cottonseed, groundnut, corn, germ, olive, castor, and sesame oils),glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fattyacid esters of sorbitan, and mixtures thereof. Besides inert diluents,the oral compositions can also include adjuvants such as wetting agents,emulsifying and suspending agents, sweetening, flavoring, and perfumingagents.

Injectable preparations, for example, sterile injectable aqueous oroleaginous suspensions may be formulated according to the known artusing suitable dispersing or wetting agents and suspending agents. Thesterile injectable preparation may also be a sterile injectablesolution, suspension or emulsion in a nontoxic parenterally acceptablediluent or solvent, for example, as a solution in 1,3-butanediol. Amongthe acceptable vehicles and solvents that may be employed are water,Ringer's solution, U.S.P. and isotonic sodium chloride solution. Inaddition, sterile, fixed oils are conventionally employed as a solventor suspending medium. For this purpose any bland fixed oil can beemployed including synthetic mono- or diglycerides. In addition, fattyacids such as oleic acid are used in the preparation of injectables.

The injectable formulations can be sterilized, for example, byfiltration through a bacterial-retaining filter, or by incorporatingsterilizing agents in the form of sterile solid compositions which canbe dissolved or dispersed in sterile water or other sterile injectablemedium prior to use.

In order to prolong the effect of a compound of the present invention,it is often desirable to slow the absorption of the compound fromsubcutaneous or intramuscular injection. This may be accomplished by theuse of a liquid suspension of crystalline or amorphous material withpoor water solubility. The rate of absorption of the compound thendepends upon its rate of dissolution that, in turn, may depend uponcrystal size and crystalline form. Alternatively, delayed absorption ofa parenterally administered compound form is accomplished by dissolvingor suspending the compound in an oil vehicle. Injectable depot forms aremade by forming microencapsule matrices of the compound in biodegradablepolymers such as polylactide-polyglycolide. Depending upon the ratio ofcompound to polymer and the nature of the particular polymer employed,the rate of compound release can be controlled. Examples of otherbiodegradable polymers include poly(orthoesters) and poly(anhydrides).Depot injectable formulations are also prepared by entrapping thecompound in liposomes or microemulsions that are compatible with bodytissues.

Compositions for rectal or vaginal administration are preferablysuppositories which can be prepared by mixing the compounds of thisinvention with suitable non-irritating excipients or carriers such ascocoa butter, polyethylene glycol or a suppository wax which are solidat ambient temperature but liquid at body temperature and therefore meltin the rectum or vaginal cavity and release the active compound.

Solid dosage forms for oral administration include capsules, tablets,pills, powders, and granules. In such solid dosage forms, the activecompound is mixed with at least one inert, pharmaceutically acceptableexcipient or carrier such as sodium citrate or dicalcium phosphateand/or a) fillers or extenders such as starches, lactose, sucrose,glucose, mannitol, and silicic acid, b) binders such as, for example,carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone,sucrose, and acacia, c) humectants such as glycerol, d) disintegratingagents such as agar-agar, calcium carbonate, potato or tapioca starch,alginic acid, certain silicates, and sodium carbonate, e) solutionretarding agents such as paraffin, f) absorption accelerators such asquaternary ammonium compounds, g) wetting agents such as, for example,cetyl alcohol and glycerol monostearate, h) absorbents such as kaolinand bentonite clay, and i) lubricants such as talc, calcium stearate,magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate,and mixtures thereof. In the case of capsules, tablets and pills, thedosage form may also comprise buffering agents.

Solid compositions of a similar type may also be employed as fillers insoft and hard-filled gelatin capsules using such excipients as lactoseor milk sugar as well as high molecular weight polyethylene glycols andthe like. The solid dosage forms of tablets, dragees, capsules, pills,and granules can be prepared with coatings and shells such as entericcoatings and other coatings well known in the pharmaceutical formulatingart. They may optionally contain opacifying agents and can also be of acomposition that they release the active ingredient(s) only, orpreferentially, in a certain part of the intestinal tract, optionally,in a delayed manner. Examples of embedding compositions that can be usedinclude polymeric substances and waxes. Solid compositions of a similartype may also be employed as fillers in soft and hard-filled gelatincapsules using such excipients as lactose or milk sugar as well as highmolecular weight polethylene glycols and the like.

The active compounds can also be in micro-encapsulated form with one ormore excipients as noted above. The solid dosage forms of tablets,dragees, capsules, pills, and granules can be prepared with coatings andshells such as enteric coatings, release controlling coatings and othercoatings well known in the pharmaceutical formulating art. In such soliddosage forms the active compound may be admixed with at least one inertdiluent such as sucrose, lactose or starch. Such dosage forms may alsocomprise, as is normal practice, additional substances other than inertdiluents, e.g., tableting lubricants and other tableting aids such amagnesium stearate and microcrystalline cellulose. In the case ofcapsules, tablets and pills, the dosage forms may also comprisebuffering agents. They may optionally contain opacifying agents and canalso be of a composition that they release the active ingredient(s)only, or preferentially, in a certain part of the intestinal tract,optionally, in a delayed manner. Examples of embedding compositions thatcan be used include polymeric substances and waxes.

Dosage forms for topical or transdermal administration of a compound ofthis invention include ointments, pastes, creams, lotions, gels,powders, solutions, sprays, inhalants or patches. The active componentis admixed under sterile conditions with a pharmaceutically acceptablecarrier and any needed preservatives or buffers as may be required.Ophthalmic formulation, ear drops, and eye drops are also contemplatedas being within the scope of this invention. Additionally, the presentinvention contemplates the use of transdermal patches, which have theadded advantage of providing controlled delivery of a compound to thebody. Such dosage forms can be made by dissolving or dispensing thecompound in the proper medium. Absorption enhancers can also be used toincrease the flux of the compound across the skin. The rate can becontrolled by either providing a rate controlling membrane or bydispersing the compound in a polymer matrix or gel.

In some embodiments, a compound of formula (I) or a pharmaceuticalcomposition thereof is administered in conjunction with an anticanceragent. As used herein, the term “anticancer agent” refers to any agentthat is administered to a subject with cancer for purposes of treatingthe cancer. Combination therapy includes administration of thetherapeutic agents concurrently or sequentially. Alternatively, thetherapeutic agents can be combined into one composition which isadministered to the patient.

Non-limiting examples of DNA damaging chemotherapeutic agents includetopoisomerase I inhibitors (e.g., irinotecan, topotecan, camptothecinand analogs or metabolites thereof, and doxorubicin); topoisomerase IIinhibitors (e.g., etoposide, teniposide, and daunorubicin); alkylatingagents (e.g., melphalan, chlorambucil, busulfan, thiotepa, ifosfamide,carmustine, lomustine, semustine, streptozocin, decarbazine,methotrexate, mitomycin C, and cyclophosphamide); DNA intercalators(e.g., cisplatin, oxaliplatin, and carboplatin); DNA intercalators andfree radical generators such as bleomycin; and nucleoside mimetics(e.g., 5-fluorouracil, capecitibine, gemcitabine, fludarabine,cytarabine, mercaptopurine, thioguanine, pentostatin, and hydroxyurea).

Chemotherapeutic agents that disrupt cell replication include:paclitaxel, docetaxel, and related analogs; vincristine, vinblastin, andrelated analogs; thalidomide, lenalidomide, and related analogs (e.g.,CC-5013 and CC-4047); protein tyrosine kinase inhibitors (e.g., imatinibmesylate and gefitinib); proteasome inhibitors (e.g., bortezomib); NF-κBinhibitors, including inhibitors of IκB kinase; antibodies which bind toproteins overexpressed in cancers and thereby downregulate cellreplication (e.g., trastuzumab, rituximab, cetuximab, and bevacizumab);and other inhibitors of proteins or enzymes known to be upregulated,over-expressed or activated in cancers, the inhibition of whichdown-regulates cell replication. In certain embodiments, a compound ofthe invention is administered in conjunction with a proteasomeinhibitor.

Another aspect of the invention relates to inhibiting HDAC6, activity ina biological sample or a patient, which method comprises administeringto the patient, or contacting said biological sample with a compound offormula (I), or a composition comprising said compound. The term“biological sample”, as used herein, generally includes in vivo, invitro, and ex vivo materials, and also includes, without limitation,cell cultures or extracts thereof; biopsied material obtained from amammal or extracts thereof; and blood, saliva, urine, feces, semen,tears, or other body fluids or extracts thereof.

Still another aspect of this invention is to provide a kit comprisingseparate containers in a single package, wherein the inventivepharmaceutical compounds, compositions and/or salts thereof are used incombination with pharmaceutically acceptable carriers to treatdisorders, symptoms and diseases where HDAC6 plays a role.

EXPERIMENTAL PROCEDURES

Definitions

-   AcOH acetic acid-   ACN acetonitrile-   ATP adenosine triphosphate-   BOC tert-butoxycarbonyl-   DCE dichloroethane-   DCM dichloromethane-   DIPEA diisopropylethyl amine-   DMF N,N-dimethylformamide-   DMFDMA N,N-dimethylformamide dimethyl acetal-   DMAP N,N-dimethylaminopyridine-   DMSO dimethylsulfoxide-   DPPA diphenylphosphoryl azide-   DTT dithiothreitol-   EDCI N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride-   EDTA ethylenediaminetetraacetic acid-   EtOAc ethyl acetate-   EtOH ethanol-   FA formic acid-   FBS fetal bovine serum-   h hours-   HATU N,N,N′,N′-tetramethyl-O-(7-azabenzotriazole-1-yl)uronium    hexafluorophosphate-   HBTU o-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium    hexafluorophosphate-   HEPES N-(2-Hydroxyethyl)piperazine-N′-(2-ethanesulfonic acid)-   HOBT 1-hydroxybenztriazole hydrate-   HRMS high resolution mass spectrum-   LAH lithium aluminum hydride-   LCMS liquid chromatography mass spectrum-   m/z mass to charge-   Me methyl-   MeOH methanol-   min minutes-   MS mass spectrum-   MTT methylthiazoletetrazolium-   MOM-Cl methyl chloromethyl ether-   MWI microwave irradiation-   NMM N-methyl morpholine-   PBS phosphate buffered saline-   PKA cAMP-dependent protein kinase-   rt room temperature-   TEA triethylamine-   TFFA trifluoroacetic anhydride-   THF tetrahydrofuran-   TMB 3,3′,5,5′-Tetramethylbenzidine-   WST    (4-[3-(4-iodophenyl)-2-(4-nitrophenyl)-2H-5-tetrazolio]-1,3-benzene    disulfonate sodium salt)

Analytical Methods

NMR

1H NMR Spectra were run on a 300 MHZ or 400 MHz Bruker NMR unlessotherwise stated.

LCMS

LCMS spectra were run on a Phenominex Luna 5 μm C18 50×4.6 mm column ona Hewlett-Packard HP1100 using one of the following gradients unlessotherwise stated

-   (1) Method Formic Acid (FA): Acetonitrile containing 0 to 100    percent 0.1% formic acid in water (2.5 ml/min for a 3 minute run).-   (2) Method Ammonium Acetate (AA): Acetonitrile containing 0 to 100    percent 10 mM ammonium acetate in water (2.5 ml/min for a 3 minute    run).

HPLC

Reverse phase preparative purification were performed on either a GilsonHPLC or Agilent A2Prep LCMS system employing a Waters Sunfire C18 10 mm19×150 mm column unless otherwise stated.

Example 1 Synthesis of methyl4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxylate

Step 1: Methyl thieno[2,3-c]pyridine-2-carboxylate

To a 50-mL round-bottom flask was added3-fluoro-4-pyridinecarboxaldehyde (0.8 mL, 8.02 mmol) andN,N-dimethylformamide (14 mL) and the solution was cooled to 0° C. Tothis solution was added potassium carbonate (1.22 g, 8.828 mmol) andmethyl 2-mercaptoacetate (0.754 mL, 8.427 mmol). The solution turned toa clear yellow solution after stirring for 10 min. After 30 min at 0°C., the reaction was warmed to room temperature and stirred over theweekend by which time a solid precipitate was formed. Water was addedprovide a homogeneous solution, which was cooled to 0° C., the solid wascollected via vacuum filtration, and washed with cold water until clearand colorless affording methyl thieno[2,3-c]pyridine-2-carboxylate (1.55g, 82%) as a white solid. LCMS: (FA) ES+ 194; ¹H NMR (d₆-DMSO, 300 MHz)δ9.37 (s, 1 H), 8.56 (d, J=5.4 Hz, 1 H), 8.26 (d, J=0.6 Hz, 1 H), 7.97(dd, J=5.4 Hz, 1.2 Hz, 1 H), 3.92 (s, 3 H).

Step 2: Methyl6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxylate

A solution of methyl thieno[2,3-c]pyridine-2-carboxylate (370 mg, 1.9mmol) and acetonitrile (7.3 mL) was stirred at 42° C. for 6 h over whichtime the formation of a precipitate was observed. Upon cooling to roomtemperature, the solvent was removed in vacuo. To the material thusobtained was added methanol (10 mL) and platinum dioxide (100 mg, 0.4mmol). The mixture was stirred under a balloon H₂ atmosphere pressurefor 4 h. The solvent was then removed under reduced pressure and theresidue obtained was partitioned between EtOAc and saturated aqueousNaHCO₃. Upon separation, the aqueous layer was extracted with EtOActhree additional times. The combined organic phases were further washedwith saturated aqueous NaHCO₃, water and brine, dried over anhydrousMgSO₄ and concentrated to give methyl6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxylate (0.4 g,95%) as an off-white solid. LCMS: (FA) ES+ 212; ¹H NMR (CDCl₃, 300 MHz)δ7.50 (s, 1 H ), 3.85 (s, 3 H ), 3.64 (m, 2H), 2.73 (m, 4 H ), 2.48 (s,3 H ).

Step 3: Methyl 4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxylate

Into a 1000-mL round-bottom flask containing methyl6-methyl-4,5,6,7-tetrahydrothieno[2,3c]pyridine-2-carboxylate (9.84 g,46.6 mmol), and 1,4-dioxane (466 mL) was added N,N-diisopropylethylamine(81.1 mL, 466 mmol). The solution was cooled to 0° C. whereuponα-chloroethyl chloroformate (50.2 mL, 466 mmol) was added dropwise. Uponcomplete addition, the solution was warmed to room temperature andstirred for 3 h. The solvent was removed in vacuo and the residueobtained was dissolved in methanol (466 mL). The clear yellow solutionheated to reflux for 3 h. Removal of the solvent under reduced pressureafforded a solid which was partitioned between dichloromethane andsaturated aqueous NaHCO₃. The aqueous layer was further extracted withdichloromethane three times. The combined organic phases were washedwith brine, dried over anhydrous MgSO₄ and concentrated. Purificationvia flash chromatography (50% EtOAc-hexanes to 1% triethylamine-99%EtOAc to 1% MeOH-1% triethylamine-98% EtOAc) afforded methyl4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxylate (5.08 g, 55%) as abrown solid. LCMS: (FA) ES+ 198; ¹H NMR (CDCl₃, 300 MHz) δ7.50 (s, 1 H), 4.04 (s, 2 H ), 3.86 (s, 3 H ), 3.12 (t, J=6.0 Hz, 2 H ), 2.66 (t,J=6.0 Hz, 2 H ).

Example 2 Synthesis of6-(2,2-dimethylpropanoyl)-N-hydroxy-4,5,6,7-tetrahydrothieno[2,3c]pyridine-2carboxamide (Compound 1)

To a solution of HBTU (38.4 mg, 0.101 mmol) and trimethylacetic acid(10.4 mg, 0.101 mmol) in DCM (2 mL) was then added triethylamine (28.3μL, 0.203 mmol). The reaction solution was stirred at room temperaturefor 30 min. A solution of methyl4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxylate (20 mg, 0.101mmol) in DCM was added in one portion. The solution was then stirred atroom temperature overnight then further heated at 36° C. for 1 h. Uponcooling to room temperature, the reaction was diluted with DCM andwashed with saturated aqueous NaHCO₃. The aqueous layer was extractedwith methylene chloride twice, the combined organic phases wereadditionally washed with water, brine, dried over anhydrous MgSO₄ andconcentrated to afford an oil residue. To the material obtained wasadded methanol (1 mL), hydroxylamine hydrochloride (28.2 mg, 0.406mmol), and potassium hydroxide (45.5 mg, 0.811 mmol). The reactionmixture was heated at 80° C. for 2 h, cooled to room temperature and thesolvent removed in vacuo. To the solid residue obtained was dissolved inDMSO (1.4 mL) and purified with Gilson prep-HPLC [202 nm, rt=5.13 (12min), 15-45% MeCN—H₂O] to afforded6-(2,2-dimethylpropanoyl)-N-hydroxy-4,5,6,7-tetrahydrothieno[2,3c]pyridine-2carboxamide (3.51 mg, 12%) as a white solid. LCMS: (FA) ES+ 283; ¹H NMR(CDCl₃, 400 MHz) δ8.13 (s, 1 H ), 6.91 (s, 1 H ), 4.44 (s, 2 H ), 3.52(t, J=5.9 Hz, 2 H ), 2.37 (t, J=5.9 Hz, 2 H ), 0.92 (s, 9 H ).

Example 3 Synthesis of6-(cyclohexylcarbonyl)-N-hydroxy-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2carboxamide (Compound 2)

The title compound was prepared in an analogous fashion to thatdescribed in Example 2. Yield: 36.2%; Purification with Gilson prep-HPLC[198 nm, rt=5.64 (12 min), 20-50% MeCN—H₂O]. LCMS: (FA) ES+ 309; ¹H NMR(MeOD, 300 MHz) δ7.30 (s, 1 H ), 4.75 (s, 2 H ), 3.83 (t, J=6.0 Hz, 2H),2.65 (m, 3 H ), 1.74 (m, 6 H ), 1.41 (m, 4 H ).

Example 4 Synthesis ofN-hydroxy-6-[(1-methylcyclohexyl)carbonyl]-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide(Compound 3)

The title compound was prepared in an analogous fashion to thatdescribed in Example 2. Yield: 22.9%; Purification with Gilson prep-HPLC[204 nm, rt=6.69 (12 min), 25-50% MeCN—H₂O]. LCMS: (FA) ES+ 323; ¹H NMR(d₆-DMSO, 400 MHz) δ9.08 (s, 1 H ), 7.31 (s, 1 H ), 4.73 (s, 2 H ), 3.78(t, J=6.0 Hz, 2 H ), 2.63 (t, J=6.0 Hz, 2H), 1.96 (m, 2 H), 1.45 (m, 2H), 1.33 (m, 6 H).

Example 5 Synthesis of6-[2-(4-chlorophenyl)-2-methylpropanoyl]-N-hydroxy-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide(Compound 4)

The title compound was prepared in an analogous fashion to thatdescribed in Example 2. Yield: 35.9%; Purification with Gilson prep-HPLC[202 nm, rt=6.68 (12 min), 25-55% MeCN—H₂O]; LCMS: (FA) ES+ 379.

Example 6 Synthesis ofN-hydroxy-6-(3-thienylcarbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2carboxamide (Compound 5)

The title compound was prepared in an analogous fashion to thatdescribed in Example 2. Yield: 12%; Purification with Gilson prep-HPLC[212 nm, rt=4.73 (12 min), 15-40% MeCN—H₂O]; LCMS: (FA) ES+ 309; ¹H NMR(d₆-DMSO, 400 MHz) δ8.72 (s, 1 H), 7.50 (q, J=1.0 Hz, 1 H), 7.26 (q;J=2.0 Hz, 1 H), 6.97 (s, 1 H), 6.87 (d, J=5.2 Hz, 1 H), 4.40 (s, 2 H),3.31 (m, 2 H), 2.35 (m, 2 H).

Example 7 Synthesis ofN-hydroxy-6-(2-phenoxybutanoyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide(Compound 6)

The title compound was prepared in an analogous fashion to thatdescribed in Example 2. Yield: 12%; LCMS: (FA) ES+ 361.

Example 8 Synthesis of6-[(5-chloro-4-methoxy-3-thienyl)carbonyl]-N-hydroxy-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide(Compound 7)

The title compound was prepared in an analogous fashion to thatdescribed in Example 2. Yield: 1.9%; LCMS: (FA) ES+ 373.

Example 9 Synthesis ofN-hydroxy-6-(4,5,6,7-tetrahydro-2H-indazol-3-ylcarbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide(Compound 8)

The title compound was prepared in an analogous fashion to thatdescribed in Example 2. Yield: 8.5%; LCMS: (FA) ES+ 347.

Example 10 Synthesis of6-(2,2-diphenylbutanoyl)-N-hydroxy-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide(Compound 9)

The title compound was prepared in an analogous fashion to thatdescribed in Example 2. Yield: 5%; LCMS: (FA) ES+ 421.

Example 11 Synthesis of6-(dicyclohexylacetyl)-N-hydroxy-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide(Compound 10)

The title compound was prepared in an analogous fashion to thatdescribed in Example 2. Yield: 8.5%; LCMS: (FA) ES+ 347.

Example 12 Synthesis ofN-hydroxy-6-{[2-methyl-4-(trifluoromethyl)-1,3-thiazol-5-yl]carbonyl}-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide(Compound 11)

The title compound was prepared in an analogous fashion to thatdescribed in Example 2. Yield: 6.2%; LCMS: (FA) ES+ 405.

Example 13 Synthesis of6-[(2,4-dimethylphenoxy)acetyl]-N-hydroxy-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide(Compound 12)

The title compound was prepared in an analogous fashion to thatdescribed in Example 2. Yield: 3.3%; LCMS: (FA) ES+ 361.

Example 14 Synthesis of6-{[1-(2-chloro-4-fluorophenyl)cyclopentyl]carbonyl}-N-hydroxy-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide(Compound 13)

The title compound was prepared in an analogous fashion to thatdescribed in Example 2. Yield: 2.4%; LCMS: (FA) ES+ 423.

Example 15 Synthesis of6-[1-adamantylcarbonyl]-N-hydroxy-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide(Compound 14)

The title compound was prepared in an analogous fashion to thatdescribed in Example 2. Yield: 1.8%; LCMS: (FA) ES+ 361.

Example 16 Synthesis ofN-hydroxy-6-{[1-(phenylsulfonyl)piperidin-2-yl]carbonyl}-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide(Compound 15)

The title compound was prepared in an analogous fashion to thatdescribed in Example 2. Yield: 3.1%; LCMS: (FA) ES+ 436.

Example 17 Synthesis ofN-hydroxy-6-[2-methyl-5-(piperidin-1-ylsulfonyl)-3-furoyl]-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide(Compound 16)

The title compound was prepared in an analogous fashion to thatdescribed in Example 2. Yield: 9.8%; LCMS: (FA) ES+ 454.

Example 18 Synthesis of6-(9H-fluoren-9-ylacetyl)-N-hydroxy-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide(Compound 17)

The title compound was prepared in an analogous fashion to thatdescribed in Example 2. Yield: 7.6%; LCMS: (FA) ES+ 405.

Example 19 Synthesis of6-[(2,2-diphenylethyl)sulfonyl]-N-hydroxy-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide(Compound 18)

A solution of 4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxylate (40mg, 0.203 mmol), 2,2-diphenylethanesulfonylchloride (114 mg, 0.406mmol), N,N-dimethylaminopyridine (2.48 mg, 0.02 mmol), and triethylamine(56.5 uL, 0.406 mmol) in 1,2-dichloroethane (0.5 mL) was stirred at roomtemperature overnight. The reaction was diluted with dichloroethane andthe solution was washed with saturated aqueous NaHCO₃. The aqueous layerwas extracted with twice with dichloroethane, the combined organicphases were washed with brine, dried over anhydrous MgSO₄ andconcentrated to give a solid residue.

To the solid obtained was added hydroxylamine hydrochloride (56.4 mg,0.811 mmol), potassium hydroxide (91 mg, 1.62 mmol), and methanol (2 mL,49 mmol). The mixture was heated at 80° C. for 3 h, cooled to roomtemperature and the solvent removed under reduced pressure. To theresidue was dissolved in DMSO (1.5 mL) purified via Gilson prep-HPLC[208 nm, rt=7.30 (12 min), 30-60% MeCN—H₂O] to afford 32.3 mg (32.4%)6-[(2,2-diphenylethyl)sulfonyl]-N-hydroxy-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2carboxamide as a white solid. LCMS: (FA) ES+ 443; ¹H NMR (MeOD, 400 MHz)δ 7.35-7.12 (m, 11 H), 4.51 (t, J=7.0 Hz, 1 H), 4.20 (s, 2 H), 3.96 (d,J=7.2 Hz, 2H), 3.28 (d, J=5.2 Hz, 2 H), 2.59 (d, J=6.0 Hz, 2 H).

Example 20 Synthesis of6-(butylsulfonyl)-N-hydroxy-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2carboxamide (Compound 19)

The title compound was prepared in an analogous fashion to thatdescribed in Example 19 Yield: 5.4%; Purification with Gilson prep-HPLC[282 nm, rt=5.74 (12 min), 20-50% MeCN—H₂O]; LCMS: (FA) ES+ 319; ¹H NMR(MeOD, 400 MHz) δ 8.10 (s, 1 H), 6.92 (s, 1 H), 4.17 (s, 2 H), 3.22 (t,J=6.0 Hz, 2 H), 2.69 (t, J=7.8 Hz, 2 H), 2.42 (t, J=5.8 Hz, 2 H), 1.35(m, 2 H), 1.07 (m, 2 H), 0.55 (t, J=7.4 Hz, 3 H).

Example 21 Synthesis of6-[(3,5-dimethylisoxazol-4-yl)sulfonyl]-N-hydroxy-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide(Compound 20)

The title compound was prepared in an analogous fashion to thatdescribed in Example 19. Yield: 5.6%; Purification with Gilson prep-HPLC[196 nm, rt=5.71 (12 min), 20-45% MeCN—H₂O]; LCMS: (FA) ES+ 358; ¹H NMR(MeOD, 400 MHz) δ 8.47 (s, 1 H), 7.26 (s, 1 H), 4.51 (s, 2 H), 3.57 (t,J=6.0 Hz, 2 H), 2.69 (q, J=7.3 Hz, 2 H), 2.65 (s, 3 H), 2.36 (s, 3 H).

Example 22 Synthesis ofN-hydroxy-6-{[4-(trifluoromethyl)phenyl]sulfonyl}-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide(Compound 21)

The title compound was prepared in an analogous fashion to thatdescribed in Example 19. Yield: 53.2%; Purification with Gilsonprep-HPLC [232 nm, rt=7.41 (12 min), 30-65% MeCN—H₂O]. LCMS: (FA) ES+407; ¹H NMR (MeOD, 400 MHz) δ 8.04 (d, J=8.0 Hz, 2 H), 7.98 (d, J=8.0Hz, 2 H), 7.24 (s, 1 H), 4.40 (s, 2 H), 3.42 (t, J=6.0 Hz, 2 H), 2.65(t, J=6.0 Hz, 2 H).

Example 23 Synthesis of6-(3,4-dihydro-2H-1,5-benzodioxepin-7-ylmethyl)-N-hydroxy-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide(Compound 22)

A solution of 7-(chloromethyl)-3,4-dihydro-2H-1,5-benzodioxepine (0.06g, 0.3 mmol) and methyl thieno[2,3-c]pyridine-2-carboxylate (0.046 g,0.24 mmol) in acetonitrile (2 mL) was heated at 40° C. overnight then at60° C. for 4 h. Upon cooling to room temperature, the solvent wasremoved under reduced pressure to afford a solid residue. The materialthus obtained was dissolved in methanol (2 mL, 49 mmol), was cooled to−78° C. under an N₂ atmosphere and sodium borohydride (54.5 mg, 1.44mmol) was added slowly in portions. Upon complete addition, the reactionmixture was allowed to warm to room temperature. The solvent was removedunder reduced pressure and the residue obtained was partitioned betweendichloroethane and water. The aqueous layer was extracted withdichloroethane (2×), the combined organic phases were dried overanhydrous MgSO₄, and concentrated to give an oil.

To the material obtained was added potassium hydroxide (108 mg, 1.92mmol), hydroxylamine hydrochloride (66.7 mg, 0.96 mmol) and methanol (2mL, 49 mmol). The reaction mixture was heated at 80° C. for 3 h. Uponcooling to room temperature, the solvent was removed under reducedpressure and the residue obtained was dissolved in DMSO (1.5 mL) andpurified via Gilson prep-HPLC [274 nm, rt=3.25 (12 min), 2-25% MeCN—H₂O]to give 17.9 mg (20.7%)6-(3,4-dihydro-2H-1,5-benzodioxepin-7-ylmethyl)-N-hydroxy-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide as a white solid. LCMS: (FA) ES+361; ¹H NMR (d₆-DMSO, 400 MHz) δ 8.21 (s, 1 H), 7.31 (s, 1 H), 6.91 (m,3H), 4.10 (m, 4 H), 3.56 (s, 4 H), 2.67 (m, 2 H), 2.61 (m, 2 H), 2.07(m, 2 H).

Example 24 Synthesis ofN-hydroxy-6-[4-(1H-pyrazol-1-yl)benzyl]-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide(Compound 23)

The title compound was prepared in an analogous fashion to thatdescribed in Example 23. Yield: 2.6%; Purification with Gilson prep-HPLC[260 nm, rt=3.26 (12 min), 2-25% MeCN—H₂O]; LCMS: (FA) ES+ 355; ¹H NMR(MeOD, 400 MHz) δ 8.36 (s, 1 H), 8.22 (m, 1 H), 7.72 (m, 3 H), 7.52 (m,2 H), 7.28 (s, 1 H), 6.52 (m, 1 H), 3.83 (s, 2 H), 3.75 (s, 2 H), 2.88(t, J=5.8 Hz, 2 H), 2.77 (t, J=5.8 Hz, 2 H).

Example 25 Synthesis ofN-hydroxy-6-[(5-methyl-2-phenyl-2H-1,2,3-triazol-4-yl)methyl]-4,5,6,7tetrahydro thieno[2,3-c]pyridine-2-carboxamide (Compound 24)

The title compound was prepared in an analogous fashion to thatdescribed in Example 23. Yield: 9.5%; Purification with Gilson prep-HPLC[272 nm, rt=4.03 (12 min), 10-30% MeCN—H₂O]; LCMS: (FA) ES+ 370; ¹H NMR(MeOD, 400 MHz) δ 8.22 (s, 1 H), 8.00 (d, J=8.8 Hz, 2 H), 7.48 (m, 1H),7.32 (tt, J=7.6, 1.2 Hz, 2 H), 3.92 (s, 2 H), 3.84 (s, 2 H), 2.95 (t,J=6.0 Hz, 2 H), 2.77 (t, J=5.8 Hz, 2 H), 2.40 (s, 3 H).

Example 26 Synthesis of6-(2,1,3-benzothiadiazol-4-ylmethyl)-N-hydroxy-4,5,6,7-tetrahydrothieno[2,3c]pyridine-2-carboxamide(Compound 25)

The title compound was prepared in an analogous fashion to thatdescribed in Example 23. Yield: 5.6%; Purification with Gilson prep-HPLC[306 nm, rt=3.02 (12 min), 2-22% MeCN—H₂O]; LCMS: (FA) ES+ 347; ¹H NMR(MeOD, 400 MHz) δ 8.32 (s, 1 H), 7.97 (m, 1 H), 7.70 (m, 2 H), 7.28 (s,1 H), 4.35 (s, 2 H), 3.86 (s, 2 H), 2.98 (t, J=5.8 Hz, 2 H), 2.78 (t,J=5.8 Hz, 2 H).

Example 27 Synthesis of ethyl4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxylate

Into a 100-mL round-bottom flask charged with 5-tert-butyl 2-ethyl6,7-dihydrothieno[3,2-c]pyridine-2,5(4H)-dicarboxylate (1 g, 3.21 mmol;prepared as described in J. Med. Chem. 2006, 49(15):4623-4637) and DCM(16 mL) was slowly added trifluoroacetic acid (1.48 mL, 19.3 mmol) at 0°C. The solution was then stirred at room temperature for 60 min. To thereaction mixture was then added saturated aqueous NaHCO₃ solution (10mL) and DCM (10 mL). Upon separation of the layers, the aqueous solutionwas further extracted with DCM (20 mL) twice. The combined organiclayers were washed with brine, dried over anhydrous MgSO₄, andconcentrated to give ethyl4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxylate (0.547 g, 81%) asan oil. LCMS: (FA) ES+ 212.

Example 28 Synthesis of5-(2,2-dimethylpropanoyl)-N-hydroxy-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxamide(Compound 26)

To a solution of HATU (104 mg, 0.274 mmol) and trimethylacetic acid (28mg, 0.274 mmol) in DCM (2 mL) was added triethylamine (104 μL, 0.203mmol). The reaction solution was stirred at room temperature for 30 min.A solution of ethyl4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxylate (20 mg, 0.101mmol; prepared as described in J. Med. Chem. 2006, 49(15):4623-4637) inDMF (0.5 mL) was added in one portion. The solution was then stirred atroom temperature overnight. The solution was then diluted with DCM andwashed with saturated aqueous NaHCO₃. The aqueous layer was extractedwith DCM twice, the combined organic phases were additionally washedwith water, brine, dried over anhydrous MgSO₄ and concentrated to affordan oil residue. To the material thus obtained was added methanol (2 mL),hydroxylamine hydrochloride (52.1 mg, 0.75 mmol), and potassiumhydroxide (84.2 mg, 1.5 mmol). The reaction mixture was heated at 80° C.for 3 h, cooled to room temperature and the solvent removed in vacuo.The solid residue obtained was dissolved in DMSO (1.4 mL) and purifiedwith Gilson prep-HPLC [282 nm, rt=5.2 (12 min), 15-40% MeCN—H₂O] toafforded white solid (16.1 mg, 24%) as a white solid. LCMS: (FA) ES+283; ¹H NMR (d₆,DMSO, 400 MHz) δ 11.13 (s, 1 H), 9.08 (s, 1 H), 7.37 (s,1 H), 4.56 (s, 2 H), 3.83 (t, J=5.8 Hz, 2 H), 2.83 (t, J=5.4 Hz, 2 H),1.22 (s, 9 H).

Example 29 Synthesis ofN-hydroxy-5-[(1-methyl-1H-pyrrol-2-yl)carbonyl]-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxamide(Compound 27)

The title compound was prepared in an analogous fashion to thatdescribed in Example 28. (18.3 mg, 24%). LCMS: (FA) ES+ 306.

Example 30 Synthesis ofN-hydroxy-5-(1-methylcyclohexanecarbonyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxamide(Compound 28)

The title compound was prepared in an analogous fashion to thatdescribed in Example 28. (21.0 mg, 26%). LCMS: (FA) ES+ 323.

Example 31 Synthesis ofN-hydroxy-5-(5-methylpyrazine-2-carbonyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxamide(Compound 29)

The title compound was prepared in an analogous fashion to thatdescribed in Example 28. (10.3 mg, 12.9%). LCMS: (FA) ES+ 319.

Example 32 Synthesis ofN-hydroxy-5-(quinolin-8-ylcarbonyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxamide(Compound 30)

The title compound was prepared in an analogous fashion to thatdescribed in Example 28. (14.9 mg, 16.9%). LCMS: (FA) ES+ 354.

Example 33 Synthesis of5-(cyclohexanecarbonyl)-N-hydroxy-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxamide(Compound 31)

The title compound, was prepared in au analogous fashion to thatdescribed in Example 28. (14.5 mg, 18.8%). LCMS: (FA) ES+ 309.

Example 34 Synthesis of5-(4-(4,6-dimethoxypyrimidin-2-yl)benzoyl)-N-hydroxy-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxamide(Compound 32)

The title compound was prepared in an analogous fashion to thatdescribed in Example 28. (18.7 mg, 20.6%). LCMS: (FA) ES+ 309.

Example 35 Synthesis of5-(adamantan-1-ylcarbonyl)-N-hydroxy-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxamide(Compound 33)

The title compound was prepared in an analogous fashion to thatdescribed in Example 28. (26.7, 41.1%); LCMS: (FA) ES+ 361.

Example 36 Synthesis ofN-hydroxy-5-{[4-(trifluoromethyl)phenyl]sulfonyl}-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxamide(Compound 34)

The title compound was prepared in an analogous fashion to thatdescribed in Example 28. Yield: 49.9%; Purification with Gilsonprep-HPLC [228 nm, rt=7.39 (12 min), 30-65% MeCN—H₂O]. LCMS: (FA) ES+407; ¹H NMR (MeOD, 400 MHz) δ 8.04 (d, J=8.0 Hz, 2H), 7.91 (d, J=8.0 Hz,2H), 7.25 (s, 1H), 4.26 (s, 2H), 3.51 (t, J=6.0 Hz, 2H), 2.89 (t, J=6.0Hz, 2H).

Example 37 Synthesis of6-{[3-(4-fluorophenyl)-5-methylisoxazol-4-yl]carbonyl}-N-hydroxy-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide(Compound 184)

The title compound was prepared in an analogous fashion to thatdescribed in Example 2. Yield: 10.5%; LCMS: (FA) ES+ 402.

Example 38 Synthesis ofN-hydroxy-3-methyl-5-[4-(trifluoromethyl)benzyl]-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxamide(Compound 68)

The title compound was prepared in an analogous fashion to thatdescribed in Example 2. Yield: 4.2%; LCMS: (FA) ES+ 385.

Example 39 Synthesis of6-[(2,4-dimethyl-1,3-thiazol-5-yl)acetyl]-N-hydroxy-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide(Compound 47)

The title compound was prepared in an analogous fashion to thatdescribed in Example 2. Yield: 11.9%; LCMS: (FA) ES+ 352.

Example 40 Synthesis ofN-hydroxy-6-[(6-hydroxypyridin-2-yl)carbonyl]-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide(Compound 81)

The title compound was prepared in an analogous fashion to thatdescribed in Example 2. Yield: 11.8%; LCMS: (FA) ES+ 320.

Example 41 Synthesis ofN-hydroxy-6-(2-(2-methylthiazol-4-yl)acetyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide(Compound 75)

The title compound was prepared in an analogous fashion to thatdescribed in Example 2. Yield: 7.4%; LCMS: (FA) ES+ 338.

Example 42 Synthesis of6-(furan-2-carbonyl)-N-hydroxy-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide(Compound 42)

The title compound was prepared in an analogous fashion to thatdescribed in Example 2. Yield: 17.7%; LCMS: (FA) ES+ 293.

Example 43 Synthesis of6-(2,5-dimethyl-3-furoyl)-N-hydroxy-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide(Compound 178)

The title compound was prepared in an analogous fashion to thatdescribed in Example 2. Yield: 22.9%; LCMS: (FA) ES+ 321.

Example 44 Synthesis of6-({3-[(2-amino-2-oxoethyl)sulfanyl]-2-thienyl}carlbonyl)-N-hydroxy-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide(Compound 56)

The title compound was prepared in an analogous fashion to thatdescribed in Example 2. Yield: 7.0%; LCMS: (FA) ES+ 398.

Example 45 Synthesis ofN⁶-[2-fluoro-5-(trifluoromethyl)phenyl]-N²-hydroxy-4,7-dihydrothieno[2,3-c]pyridine-2,6(5H)-dicarboxamide(Compound 106)

The title compound was prepared in an analogous fashion to thatdescribed in Example 2. Yield: 5.2%; LCMS: (FA) ES+ 389.

Example 46 Synthesis ofN-hydroxy-6-(quinolin-2-ylcarbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide(Compound 179)

The title compound was prepared in an analogous fashion to thatdescribed in Example 2. Yield: 7.1%; LCMS: (FA) ES+ 354.

Example 47 Synthesis ofN-hydroxy-6-[(5-methyl-2-phenyl-1,3-oxazol-4-yl)acetyl]-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide(Compound 65)

The title compound was prepared in an analogous fashion to thatdescribed in Example 2. Yield: 17.2%; LCMS: (FA) ES+ 398.

Example 48 Synthesis of6-(3,5-difluorobenzoyl)-N-hydroxy-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide(Compound 140)

The title compound was prepared in an analogous fashion to thatdescribed in Example 2. Yield: 7.7%; LCMS: (FA) ES+ 339.

Example 49 Synthesis ofN-hydroxy-6-(2-methyl-4-phenylpyrimidine-5-carbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide(Compound 48)

The title compound was prepared in an analogous fashion to thatdescribed in Example 2. Yield: 16.8%; LCMS: (FA) ES+ 395.

Example 50 Synthesis ofN-hydroxy-6-(2,3,5,6-tetrafluorobenzoyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide(Compound 156)

The title compound was prepared in an analogous fashion to thatdescribed in Example 2. Yield: 5.8%; LCMS: (FA) ES+ 375.

Example 51 Synthesis of6-[(4,6-dimethoxypyrimidin-2-yl)carbonyl]-N-hydroxy-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide(Compound 100)

The title compound was prepared in an analogous fashion to thatdescribed in Example 2. Yield: 5.8%; LCMS: (FA) ES+ 365.

Example 53 Synthesis of6-[(4-tert-butylphenyl)acetyl]-N-hydroxy-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide(Compound 118)

The title compound was prepared in an analogous fashion to thatdescribed in Example 2. Yield: 12.7%; LCMS: (FA) ES+ 373.

Example 54 Synthesis of6-(2-(3,5-dimethyl-1H-pyrazol-1-yl)acetyl)-N-hydroxy-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide(Compound 125)

The title compound was prepared in an analogous fashion to thatdescribed in Example 2. Yield: 6.3%; LCMS: (FA) ES+ 335.

Example 55 Synthesis ofN-hydroxy-6-[(4-methyl-1,3-thiazol-5-yl)carbonyl]-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide(Compound 98)

The title compound was prepared in an analogous fashion to thatdescribed in Example 2. Yield: 14.6%; LCMS: (FA) ES+ 324.

Example 56 Synthesis ofN-hydroxy-6-(quinoline-6-carbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide(Compound 95)

The title compound was prepared in an analogous fashion to thatdescribed in Example 2. Yield: 11.6%; LCMS: (FA) ES+ 354.

Example 57 Synthesis ofN-hydroxy-6-[(1-phenyl-1H-pyrazol-4-yl)carbonyl]-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide(Compound 127)

The title compound was prepared in an analogous fashion to thatdescribed in Example 2. Yield: 6.3%; LCMS: (FA) ES+ 369.

Example 58 Synthesis of6-[(1-ethyl-3-methyl-1H-pyrazol-5-yl)carbonyl]-N-hydroxy-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide(Compound 149)

The title compound was prepared in an analogous fashion to thatdescribed in Example 2. Yield: 22.4%; LCMS: (FA) ES+ 335.

Example 59 Synthesis of6-[(3,5-dimethylisoxazol-4-yl)carbonyl]-N-hydroxy-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide(Compound 177)

The title compound was prepared in an analogous fashion to thatdescribed in Example 2. Yield: 21.3%; LCMS: (FA) ES+ 322.

Example 60 Synthesis ofN-hydroxy-6-[(5-methyl-3-phenylisoxazol-4-yl)carbonyl]-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide(Compound 107)

The title compound was prepared in an analogous fashion to thatdescribed in Example 2. Yield: 5.5%; LCMS: (FA) ES+ 384.

Example 61 Synthesis ofN-hydroxy-6-(3-methyl-2-furoyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide(Compound 94)

The title compound was prepared in an analogous fashion to thatdescribed in Example 2. Yield: 18.3%; LCMS: (FA) ES+ 307.

Example 62 Synthesis of6-[(1-tert-butyl-3-methyl-1H-pyrazol-5-yl)carbonyl]-N-hydroxy-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide(Compound 69)

The title compound was prepared in an analogous fashion to thatdescribed in Example 2. Yield: 16.7%; LCMS: (FA) ES+ 363.

Example 63 Synthesis of6-[3,5-bis(trifluoromethyl)benzoyl]-N-hydroxy-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide(Compound 36)

The title compound was prepared in an analogous fashion to thatdescribed in Example 2. Yield: 5.7%; LCMS: (FA) ES+ 439.

Example 64 Synthesis of6-(2-(3,5-dimethylisoxazol-4-yl)acetyl)-N-hydroxy-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide(Compound 62)

The title compound was prepared in an analogous fashion to thatdescribed in Example 2. Yield: 8.3%; LCMS: (FA) ES+ 336.

Example 65 Synthesis ofN-hydroxy-6-[(1-methyl-1H-pyrrol-2-yl)carbonyl]-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide(Compound 116)

The title compound was prepared in an analogous fashion to thatdescribed in Example 2. Yield: 19.5%; LCMS: (FA) ES+ 306.

Example 66 Synthesis of6-(2-(3,5-difluorophenyl)acetyl)-N-hydroxy-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide(Compound 52)

The title compound was prepared in an analogous fashion to thatdescribed in Example 2. Yield: 4.6%; LCMS: (FA) ES+ 353.

Example 67 Synthesis of6-(4-fluoro-3-methylbenzoyl)-N-hydroxy-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide(Compound 51)

The title compound was prepared in an analogous fashion to thatdescribed in Example 2. Yield: 20.1%; LCMS: (FA) ES+ 335.

Example 68 Synthesis of6-[(3-tert-butyl-1-methyl-1H-pyrazol-5-yl)carbonyl]-N-hydroxy-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide(Compound 88)

The title compound was prepared in an analogous fashion to thatdescribed in Example 2. Yield: 24.5%; LCMS: (FA) ES+ 363.

Example 69 Synthesis ofN-hydroxy-6-(2-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide(Compound 93)

The title compound was prepared in an analogous fashion to thatdescribed in Example 2. Yield: 7.7%; LCMS: (FA) ES+ 389.

Example 70 Synthesis of6-(4-tert-butylbenzoyl)-N-hydroxy-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide(Compound 64)

The title compound was prepared in an analogous fashion to thatdescribed in Example 2. Yield: 20.9%; LCMS: (FA) ES+ 359.

Example 71 Synthesis of6-(5-tert-butyl-2-methyl-3-furoyl)-N-hydroxy-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide(Compound 67)

The title compound was prepared in an analogous fashion to thatdescribed in Example 2. Yield: 20.2%; LCMS: (FA) ES+ 363.

Example 72 Synthesis of6-[3,5-bis(acetylamino)benzoyl]-N-hydroxy-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide(Compound 131)

The title compound was prepared in an analogous fashion to thatdescribed in Example 2. Yield: 8.0%; LCMS: (FA) ES+ 417.

Example 73 Synthesis of6-[(3-ethyl-1-methyl-1H-pyrazol-5-yl)carbonyl]-N-hydroxy-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide(Compound 186)

The title compound was prepared in an analogous fashion to thatdescribed in Example 2. Yield: 17.2%; LCMS: (FA) ES+ 335.

Example 74 Synthesis of6-(3-(1H-pyrazol-1-yl)benzoyl)-N-hydroxy-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide(Compound 133)

The title compound was prepared in an analogous fashion to thatdescribed in Example 2. Yield: 7.2%; LCMS: (FA) ES+ 369.

Example 75 Synthesis of6-(4-fluorobenzoyl)-N-hydroxy-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide(Compound 182)

The title compound was prepared in an analogous fashion to thatdescribed in Example 2. Yield: 19.3%; LCMS: (FA) ES+ 321.

Example 76 Synthesis ofN-hydroxy-6-(4-(trifluoromethyl)benzoyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide(Compound 171)

The title compound was prepared in an analogous fashion to thatdescribed in Example 2. Yield: 8.4%; LCMS: (FA) ES+ 371.

Example 77 Synthesis ofN-hydroxy-6-(quinoline-8-carbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide(Compound 99)

The title compound was prepared in an analogous fashion to thatdescribed in Example 2. Yield: 10.1%; LCMS: (FA) ES+ 354.

Example 78 Synthesis ofN-hydroxy-6-({[3-(trifluoromethyl)phenyl]sulfanyl}acetyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide(Compound 89)

The title compound was prepared in an analogous fashion to thatdescribed in Example 2. Yield: 11.0%; LCMS: (FA) ES+ 417.

Example 79 Synthesis ofN-hydroxy-6-[(5-methyl-1-phenyl-1H-pyrazol-4-yl)carbonyl]-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide(Compound 84)

The title compound was prepared in an analogous fashion to thatdescribed in Example 2. Yield: 22.7%; LCMS: (FA) ES+ 383.

Example 80 Synthesis ofN-hydroxy-6-(1,3-thiazol-4-ylcarbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide(Compound 146)

The title compound was prepared in an analogous fashion to thatdescribed in Example 2. Yield: 12.8%; LCMS: (FA) ES+ 310.

Example 81 Synthesis ofN-hydroxy-6-[(4-methyl-2-phenylpyrimidin-5-yl)carbonyl]-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide(Compound 152)

The title compound was prepared in an analogous fashion to thatdescribed in Example 2. Yield: 17.2%; LCMS: (FA) ES+ 395.

Example 82 Synthesis ofN2-hydroxy-N-6-(4-methylbenzyl)-4,5-dihydrothieno[2,3-c]pyridine-2,6(5H)-dicarboxamide(Compound 103)

To a vial charged with 1-(isocyanatomethyl)-4-methylbenzene (0.032 g,0.22 mmol) was addedmethyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxylate (0.0434 g,0.22 mmol) in 1,2-dichloroethane (2 mL). The solution was stirred at rtfor 2 h. The solvent was evaporated. To the residue was added potassiumhydroxide (0.099 g, 1.76 mmol), hydroxylamine hydrochloride (0.046 g0.66 mmol), and methanol (2 mL). The vial was capped and heated at 80°C. with vigorous shaking for 1 h, then cooled to rt. To the vial wasadded acetic acid (0.1 mL) and the solution was shaken at rt for 15 min.The solvent was completed removed. To the residue was added DMSO (1.3mL) and the solution was filtered and purified by Gilson prep-HPLC toafford 0.007 g (11.2%) of a white solid. LCMS: (FA) ES+ 346.

Example 83 Synthesis ofN²-hydroxy-N⁶-(5-methyl-3-phenylisoxazol-4-yl)-4,7-dihydrothieno[2,3-c]pyridine-2,6(5H)-dicarboxamide(Compound 132)

The title compound was prepared in an analogous fashion to thatdescribed in Example 82. Yield: 20.4%; LCMS: (FA) ES+ 399.

Example 84 Synthesis ofN²-hydroxy-N⁶-(3-methylphenyl)-4,7-dihydrothieno[2,3-c]pyridine-2,6(5H)-dicarboxamide(Compound 80)

The title compound was prepared in an analogous fashion to thatdescribed in Example 82. Yield: 4.8%; LCMS: (FA) ES+ 332.

Example 85 Synthesis ofN²-hydroxy-N⁶-[3-(trifluoromethyl)phenyl]-4,7-dihydrothieno[2,3-c]pyridine-2,6(5H)-dicarboxamide(Compound 54)

The title compound was prepared in an analogous fashion to thatdescribed in Example 82. Yield: 3.6%; LCMS: (FA) ES+ 386.

Example 86 Synthesis ofN⁶-(4-butylphenyl)-N²-hydroxy-4,7-dihydrothieno[2,3-c]pyridine-2,6(5H)-dicarboxamide(Compound 169)

The title compound was prepared in an analogous fashion to thatdescribed in Example 82. Yield: 12.1%; LCMS: (FA) ES+ 374.

Example 87 Synthesis ofN²-hydroxy-N⁶-(5-phenyl-2-thienyl)-4,7-dihydrothieno[2,3-c]pyridine-2,6(5H)-dicarboxamide(Compound 40)

The title compound was prepared in an analogous fashion to thatdescribed in Example 82. Yield: 6.8%; LCMS: (FA) ES+ 400.

Example 88 Synthesis ofN²-hydroxy-N⁶-mesityl-4,7-dihydrothieno[2,3-c]pyridine-2,6(5H)-dicarboxamide(Compound 176)

The title compound was prepared in an analogous fashion to thatdescribed in Example 82. Yield: 26.3%; LCMS: (FA) ES+ 360.

Example 89 Synthesis ofN²-hydroxy-N⁶-(4-isopropylphenyl)-4,7-dihydrothieno[2,3-c]pyridine-2,6(5H)-dicarboxamide(Compound 139)

The title compound was prepared in an analogous fashion to thatdescribed in Example 82. Yield: 5.2%; LCMS: (FA) ES+ 360.

Example 90 Synthesis ofN⁶-cyclohexyl-N²-hydroxy-4,7-dihydrothieno[2,3-c]pyridine-2,6(5H)-dicarboxamide(Compound 76)

The title compound was prepared in an analogous fashion to thatdescribed in Example 82. Yield: 20.1%; LCMS: (FA) ES+ 324.

Example 91 Synthesis ofN²-hydroxy-N⁶-(4-iodophenyl)-4,7-dihydrothieno[2,3-c]pyridine-2,6(5H)-dicarboxamide(Compound 163)

The title compound was prepared in an analogous fashion to thatdescribed in Example 82. Yield: 13.2%; LCMS: (FA) ES+ 444.

Example 92 Synthesis of ethyl3-methyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxylate

Step 1: ethyl 3-methylthieno[3,2-c]pyridine-2-carboxylate

To a solution of ethyl 2-mercaptoacetate (5.52 g, 0.046 mol) andtriethylamine (5.52 g, 0.055 mol) in acetonitrile (100 mL) at roomtemperature was added 1-(4-chloropyridin-3-yl)ethanone (6.5 g, 0.042mol). The reaction mixture was heated at reflux for 18 hours. Uponcooling to room temperature, the solvent was evaporated and the residueobtained partitioned between ethyl acetate and water. The organic layerwas dried over anhydrous NaHSO₄, filtered and concentrated. The oilyresidue was passed through a pad of silica (ethyl acetate/hexane: 5/1)to afford ethyl 3-methylthieno[3,2-c]pyridine-2-carboxylate (1.6 g,22%). LCMS (FA) ES+ 222; ¹H NMR (400 MHz, CDCl₃) δ 9.10 (s, 1H), 8.50(d, J=5.6 Hz, 1H), 7.98 (d, J=17.6 Hz, 1H), 4.37 (d, J=7.2 Hz, 2H), 3.58(t, J=5.9 Hz, 2H), 1.38 (d, J=7.2 Hz, 3H).

Step 2: ethyl3-methyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxylate

A mixture of ethyl 3-methylthieno[3,2-c]pyridine-2-carboxylate (4 g,0.018 mol) and PtO₂ (0.5 g, 0.002 mol) in ethanol (100 mL) was stirredunder an H₂ atmosphere (3 atmospheres) for 72 hours at room temperature.The PtO₂ was removed by filtration, the filtrate was concentrated underreduced pressure and the residue obtained was purified by silica gelchromatography (DCM/EtOH=10:1) to afford ethyl3-methyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxylate (1.6 g,40%). ES+ 226; ¹H NMR (400 MHz, DMSO) δ 4.24 (q, J=7.1 Hz, 2H), 3.93 (s,2H), 3.21 (t, J=5.9 Hz, 2H), 2.89 (t, J=5.7 Hz, 2H), 2.55 (s, 1H), 2.34(s, 3H), 1.26 (t, J=6.0 Hz, 3H).

Example 93 Synthesis of7,7-dimethyl-N-(tetrahydro-2H-pyran-2-yloxy)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxamide

Step 1:1-benzyl-4-chloro-5,5-dimethyl-1,2,5,6-tetrahydropyridine-3-carbaldehyde

A solution of anhydrous DMF (142 mL, 1.85 mol) in anhydrous DCM (670 mL)was cooled to 0° C. A solution of POCl₃ (121 mL, 1.3 mol) in anhydrousDCM (87 mL) was added dropwise. Upon complete addition, the solution waswarmed to room temperature and further to reflux for 30 minutes. Asolution of 1-benzyl-3,3-dimethylpiperidin-4-one (75 g, 0.35 mol) inanhydrous DCM (133 mL) was added all at once to the boiling solution andthe mixture was further refluxed overnight. The reaction was cooled toroom temperature and added dropwise to a biphasic mixture of 4.0 Maqueous sodium acetate (1000 mL) and DCM (300 mL). Upon separation ofthe layers, the organic layer was washed with water, dried overanhydrous Na₂SO₄ and concentrated to dryness to afford1-benzyl-4-chloro-5,5-dimethyl-1,2,5,6-tetrahydropyridine-3-carbaldehyde(75 g, 82% crude yield).

Step 2: ethyl5-benzyl-7,7-dimethyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxylate

To a solution of1-benzyl-4-chloro-5,5-dimethyl-1,2,5,6-tetrahydropyridine-3-carbaldehyde(75 g, 0.28 mol) in DCM (1.2 L) was added ethyl 2-mercaptoacetate (67 g,0.56 mol) and triethylamine (85 g, 0.84 mol) was added slowly at roomtemperature. Upon complete addition, the reaction mixture was heated atreflux overnight. Upon cooling to room temperature, the reaction wasquenched with the addition of water. The organic layer was washed withwater, dried over anhydrous Na₂SO₄, concentrated and purified by silicagel chromatography (0-20% EtOAc/hexane) to afford the title compound(31.7 g, 27.5% over two steps).

Step 3: ethyl7,7-dimethyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxylatehydrochloride

A solution of ethyl5-benzyl-7,7-dimethyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxylate(14.6 g, 0.044 mol) in anhydrous DCM was cooled to 0° C. whereupon K₂CO₃(6.1 g, 0.044 mmol) and α-chloroethyl chloroformate (6.97 g, 0.049 mol)were added. Upon complete addition, the reaction was heated at refluxovernight. The reaction was cooled to room temperature and diluted withDCM, then washed with saturated aqueous NaHCO₃ and brine respectively.The organic layer was dried over anhydrous Na₂SO₄ and evaporated toafford an oily residue which was taken up in EtOH and refluxed for 2hours. The solvent was evaporated to dryness and the residue was washedwith ethyl acetate to afford the desired product (9.6 g, 79%). ¹H NMR(400 MHz, DMSO) δ 9.82 (s, 2H), 7.64 (s, 1H), 4.28 (q, J=7.2 Hz, 2H),4.15 (s, 2H), 3.26 (s, 2H), 1.42 (s, 6H), 1.28 (t, J=7.2 Hz, 3H).

Step 4: ethyl7,7-dimethyl-5-(2-nitrophenylsulfonyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxylate

A solution of ethyl7,7-dimethyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxylate (20.5g, 0.074 mol) and DIPEA (42.8 g, 0.37 mol) in DCM (400 mL) was cooled to0° C. 2-nitrobenzene-1-sulfonyl chloride (17.3 g, 0.078 mol) was thenadded and the reaction mixture was allowed to warm to room temperatureovernight. The crude reaction solution was applied directly to a silicagel column and purified (10-20% EtOAc/hexane) to afford product (27.6 g,88%). ¹H NMR (400 MHz, CDCl₃) δ 7.98 (dd, J=4.8, 2.4 Hz, 1H), 7.64-7.68(m, 2H), 7.57 (dd, J=4.4, 2.4 Hz, 1H), 7.37 (s, 1H), 7.19 (s, 1H), 4.33(s, 2H), 4.25 (q, J=7.2 Hz, 2H), 3.33 (s, 2H), 1.31 (s, 6H), 1.19 (t,J=7.2 Hz, 3H),

Step 5:7,7-dimethyl-5-(2-nitrophenylsulfonyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxylicacid

To a solution of ethyl7,7-dimethyl-5-(2-nitrophenylsulfonyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxylate(32.6 g, 76.8 mmol) in THF (853 mL) was added 1.0 M aqueous LiOH (307mL, 307 mmol) and the reaction mixture stirred overnight at roomtemperature. The solution was concentrated and the residue dissolved inwater (100 mL) and neutralized with 1.0 M aqueous HCl (307 mL). Theresulting precipitate was collected via vacuum filtration to affordwhite solid (29 g, 95%). LCMS (FA) ES+ 397; ¹H NMR (400 MHz, DMSO) δ13.04 (s, 1H), 8.08 (dd, J=7.6, 1.6 Hz, 1H), 8.02 (dd, J=7.7, 1.5 Hz,1H), 7.95-7.86 (m, 2H), 7.49 (s, 1H), 4.36 (s, 2H), 3.40 (s, 2H), 1.28(s, 6H).

Step 6:7,7-dimethyl-5-(2-nitrophenylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxamide

A solution of7,7-dimethyl-5-(2-nitrophenylsulfonyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxylicacid (20 g, 50 mmol) was cooled to 0° C. DIPEA (32.3 g, 250 mmol) wasadded and the solution was stirred at 0° C. for 30 minutes.O-(tetrahydro-2H-pyran-2-yl)hydroxylamine (5.8 g, 50 mmol) and HATU(22.8 g, 60 mmol) were then added and the reaction was allowed to warmto room temperature overnight. The reaction mixture was washed withwater, brine and dried over anhydrous Na₂SO₄, concentrated and purifiedby silica gel chromatography (20-50% EtOAc/hexane) to afford product(23.5 g, 94%). LCMS (FA) ES+ 496; ¹H NMR (400 MHz, DMSO) δ 11.60 (s,1H), 8.10 (dd, J=7.7, 1.5 Hz, 1H), 8.02 (dd, J=7.7, 1.5 Hz, 1H), 7.90(dtd, J=17.6, 7.5, 1.4 Hz, 2H), 7.41 (s, 1H), 4.92 (s, 1H), 4.33 (s,2H), 4.00 (s, 1H), 3.50 (d, J=11.1 Hz, 1H), 3.38 (s, 2H), 1.72 (d,J=22.2 Hz, 3H), 1.53 (s, 3H), 1.27 (s, 6H).

Step 7:7,7-dimethyl-N-(tetrahydro-2H-pyran-2-yloxy)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxamide

To a mixture of7,7-dimethyl-5-(2-nitrophenylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxamide(15.4 g, 31 mmol) and cesium carbonate (20.2 g, 62 mmol) in acetonitrile(800 mL) was added a solution of thiophenol (6.85 g, 62 mmol) inacetonitrile (70 mL). The reaction mixture was stirred at roomtemperature overnight. The solvent was removed in vacuo and the residueapplied to silica gel chromatography (0-20% DCM/MeOH) to afford thetitle compound (8.2 g, 85%). LCMS (FA) ES+ 311; ¹H NMR (400 MHz, DMSO) δ11.49 (s, 1H), 7.30 (s, 1H), 4.91 (s, 1H), 4.01 (dd, J=15.6, 8.0 Hz,1H), 3.71 (s, 2H), 3.55-3.44 (m, 1H), 2.71 (s, 2H), 1.69 (s, 3H), 1.53(s, 3H), 1.25 (s, 6H).

Example 94 Synthesis ofN-hydroxy-3-methyl-5-[(1-methyl-1H-pyrrol-2-yl)carbonyl]-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxamide(Compound 194)

Step 1: ethyl3-methyl-5-(1-methyl-1H-pyrrole-2-carbonyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxylate

A solution of N-methylpyrrole-2-carboxylic acid (12.5 mg, 0.1 mmol),N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uroniumhexafluorophosphate (0.048 g, 0.11 mmol) and N,N-diisopropylethylamine(52.2 μL, 0.3 mmol) in N,N-dimethylformamide (1 mL, 12.9 mmol) wasstirred at room temperature for 15 minutes. A solution of ethyl3-methyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxylate (22.5 mg,0.1 mmol) in N,N-dimethylformamide (1 mL) was then added and thereaction was further stirred at room temperature overnight. The solutionwas evaporated to dryness and the residue obtained was partitionedbetween DCM (2 mL) and half-saturated aqueous sodium bicarbonatesolution (2 mL). Upon separation of the layers, the aqueous layer wasextracted with additional DCM (2 mL) and the combined organic layerswere concentrated to dryness.

Step 2:N-hydroxy-3-methyl-5-[(1-methyl-1H-pyrrol-2-yl)carbonyl]-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxamide

A mixture of hydroxylamine hydrochloride (2 g, 29 mmol) in methanol (10mL) was heated at 90° C. under a dry nitrogen atmosphere untilhomogenous. To the heated solution was added a solution of potassiumhydroxide (2.85 g, 50.8 mmol) in methanol (6 mL). The formation of awhite precipitate was observed. After heating at 90° C. for 30 minutes,the mixture was cooled to room temperature and the solids allowed tosettle. The resulting solution was assumed to have a 1.7 M concentrationof hydroxylamine•potassium salt and was carefully removed by syringe toexclude solids. An aliquot of the above solution (1 mL, 1.7 mmol) wasadded to a solution of ethyl3-methyl-5-(1-methyl-1H-pyrrole-2-carbonyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxylateobtained in the previous step dissolved in methanol (1 mL). Afterstirring for 30 minutes at room temperature, the reaction was quenchedwith the addition of formic acid (0.1 mL, 3 mmol). The reaction mixturewas concentrated to dryness and the residue obtained redissolved in DMSO(1 mL) and purified by reverse phase Gilson prep-HPLC to afford thetitle compound as a white solid (7.2 mg, 22.5% over two steps). LCMS(FA) ES+ 320; ¹H NMR (400 MHz, DMSO) δ 6.93-6.92 (m, 1H), 6.44 (dd,J=3.8, 1.6 Hz, 1H), 6.06 (dd, J=3.7, 2.6 Hz, 1H), 4.55 (s, 2H), 3.88 (t,J=5.6 Hz, 2H), 3.67 (s, 3H), 2.88 (d, J=2.8 Hz, 2H), 2.22 (s, 3H).

Example 95

The following compounds were prepared in a fashion analogous to thatdescribed in Example 94 starting from the intermediates which wereprepared as described above and the corresponding carboxylic acids.

LC-MS Compound Structure (FA) 221

ES+ 407 219

ES+ 331 233

ES+ 393 204

ES+ 297 209

ES+ 347 225

ES+ 373 229

ES+ 283 217

ES+ 318 232

ES+ 337 216

ES+ 357 199

ES+ 415 197

ES+ 338 205

ES+ 373 203

ES+ 375 193

ES+ 351

Example 96 Synthesis of5-[(3-chloro-1-benzothien-2-yl)carbonyl]-N-hydroxy-7,7-dimethyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxamide(Compound 192)

Step 1: ethyl5-(3-chlorobenzo[b]thiophene-2-carbonyl)-7,7-dimethyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxylate

A solution of 3-chloro-1-benzothiophene-2-carboxylic acid (23.4 mg, 0.11mmol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uroniumhexafluorophosphate (0.048 g, 0.11 mmol) and N,N-diisopropylethylamine(52.2 μL, 0.3 mmol) in N,N-dimethylformamide (1 mL, 12.9 mmol) wasstirred at room temperature for 15 minutes. A solution of7,7-dimethyl-N-(tetrahydro-2H-pyran-2-yloxy)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxamide(31 mg, 0.1 mmol) in N,N-dimethylformamide (1 mL) was then added and thereaction was further stirred at room temperature overnight. The solutionwas evaporated to dryness and the residue obtained was partitionedbetween DCM (2 mL) and half-saturated aqueous sodium bicarbonatesolution (2 mL). Upon separation of the layers, the aqueous layer wasextracted with additional DCM (2 mL) and the combined organic layerswere concentrated to dryness to afford the title compound.

Step 2:5-[(3-chloro-1-benzothien-2-yl)carbonyl]-N-hydroxy-7,7-dimethyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxamide

To a solution of ethyl5-(3-chlorobenzo[b]thiophene-2-carbonyl)-7,7-dimethyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxylateobtained in step 1 in THF (0.5 mL) was added 4.0 M HCl in 1,4-dioxane(0.5 mL, 2 mmol). The reaction was stirred at room temperature for 2hours whereupon it was concentrated to dryness. The residue obtained wasredissolved in DMSO (1 mL) and purified on Gilson prep-HPLC to affordthe title compound (6.7 mg, 16% over two steps). LCMS (FA) ES+ 421; ¹HNMR (400 MHz, DMSO) δ 8.16-8.11 (m, 1H), 7.89-7.83 (m, 1H), 7.63-7.55(m, 2H), 7.46-7.12 (m, 1H), 4.64 (d, J=104.6 Hz, 2H), 3.88-3.49 (m, 2H),1.36 (br s, 3H), 1.20 (br s, 3H).

Example 97

The following compounds were prepared in a fashion analogous to thatdescribed in Example 96 starting from the intermediates which wereprepared as described above and the corresponding carboxylic acids.

LC-MS Compound Structure (FA) 211

ES+ 414 226

ES+ 337 220

ES+ 332 215

ES+ 371 207

ES+ 407 208

ES+ 446 214

ES+ 361 234

ES+ 365 210

ES+ 334 222

ES+ 352 218

ES+ 365 198

ES+ 403 228

ES+ 429 224

ES+ 351 195

ES+ 387 227

ES+ 445 190

ES+ 387

Example 98 Synthesis ofN²-hydroxy-7,7-dimethyl-N5-[(1S)-1-phenylethyl]-6,7-dihydrothieno[3,2-c]pyridine-2,5(4H)-dicarboxamide(Compound 201)

A solution of7,7-dimethyl-N-(tetrahydro-2H-pyran-2-yloxy)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxamide(31 mg, 0.1 mmol) and triethylamine (41.8 μL, 0.3 mmol) in1,2-dichloroethane (1 mL) was added (S)-1-phenylethyl isocyanate (22.1mg, 0.15 mmol). The reaction was stirred at room temperature overnight.The solution was evaporated to dryness and the residue obtained wasredissolved in tetrahydrofuran (1 mL). 4.0 M of hydrochloric acid in1,4-dioxane (1 mL, 4 mmol) was added and the reaction solution wasstirred at room temperature for 2 hours. The solution was evaporated todryness, redissolved in DMSO (1 mL) and purified on an Agilent 1100LC/MSD instrument to afford the title compound (17.8 mg, 46%). LCMS (FA)ES+ 374; ¹H NMR (400 MHz, MeOD) δ 7.35-7.24 (m, 5H), 7.20-7.15 (m, 1H),5.01-4.91 (m, 1H), 4.50 (d, J=4.0 Hz, 2H), 3.50 (d, J=4.6 Hz, 2H), 1.47(d, J=7.1 Hz, 3H), 1.30 (s, 6H).

Example 99

The following compounds were prepared in a fashion analogous to thatdescribed in Example 98 starting from the intermediates which wereprepared as described above and the corresponding isocyanates.

LC-MS Compound Structure (FA) 213

ES+ 374 196

ES+ 371 189

ES+ 382 200

ES+ 374 206

ES+ 387 202

ES+ 374 191

ES+ 360

Example 100 Synthesis of tert-butyl2-[(hydroxyamino)carbonyl]-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-carboxylate(Compound 212)

A mixture of 5-tert-butyl 2-ethyl6,7-dihydrothieno[3,2-c]pyridine-2,5(4H)-dicarboxylate (0.056 g, 0.18mmol; prepared as described in J. Med. Chem. 2006, 49(15): 4623),hydroxylamine hydrochloride (0.037 mg, 0.54 mmol) and potassiumhydroxide (0.1 mg, 1.8 mmol) in methanol (2 mL) was heated at 75° C. for1 hour. Upon cooling to room temperature the reaction was quenched bythe addition of acetic acid (100 μL, 1.8 mmol) and the solvent wasevaporated to dryness. The residue was dissolved in DMSO (1 mL) andpurified using a Gilson prep to afford a white solid (26.9 mg, 50%).LCMS (FA) ES+ 299; ¹H NMR (400 MHz, MeOD) δ 7.27 (s, 1H), 4.46 (s, 2H),3.71 (t, J=5.4 Hz, 2H), 2.84 (t, J=5.7 Hz, 2H), 1.48 (s, 9H).

Example 101 Synthesis of methyl5,6-dihydro-4H-thieno[2,3-c]pyrrole-2-carboxylate

Step 1: methyl 4,5-bis(chloromethyl)thiophene-2-carboxylate

A solution of methyl thiophene-2-carboxylate (1 mL, 8.65 mmol) inchloromethyl methyl ether (1 mL, 13 mmol) was added dropwise to asuspension of zinc chloride (1.179 g, 8.65 mmol) in chloromethyl methylether (8 mL, 104 mmol) under an N₂ atmosphere. After complete addition,the mixture was stirred at room temperature for 15 minutes over whichtime the suspension became a homogenous clear colorless solution. Thereaction was further warmed to 60° C. for 3 hours. The reaction mixturewas cooled to room temperature and poured over ice. The mixture wasstirred for 1 hour then extracted with EtOAc (30 mL). The organic layerwas dried over anhydrous MgSO₄, concentrated and purified via silicachromatography (5-10% EtOAc/hexane) to afford a colorless solid (1.272g, 61%). ¹H NMR (400 MHz, CDCl₃) δ 7.71 (s, 1H), 4.78 (s, 2H), 4.59 (s,2H), 3.89 (s, 3H).

Step 2: methyl5-[(2-nitrophenyl)sulfonyl]-5,6-dihydro-4H-thieno[2,3-c]pyrrole-2-carboxylate

To a solution of methyl 4,5-bis(chloromethyl)thiophene-2-carboxylate(4.106 g, 17.17 mmol) and 2-nitrobenzenesulfonamide (3.825 g, 18.92mmol) in acetone (40 mL) was added 2.5 M of potassium carbonate in water(20 mL, 50 mmol). The resulting biphasic mixture was stirred at roomtemperature for 1 hour then further heated at 45° C. overnight resultingin formation of precipitate. The reaction mixture was cooled to roomtemperature and the precipitate was collected by vacuum filtration. Thesolid obtained was washed with water followed by cold methanol and driedunder vacuum to afford an off white solid (3.352 g, 53%). LCMS (FA) ES+369; ¹H NMR (400 MHz, DMSO) δ 8.02 (ddd, J=7.8, 4.9, 1.4 Hz, 2H), 7.90(td, J=7.7, 1.5 Hz, 1H), 7.84 (td, J=7.7, 1.4 Hz, 1H), 7.63 (s, 1H),4.79 (t, J=2.9 Hz, 2H), 4.60 (t, J=2.9 Hz, 2H), 3.80 (s, 3H).

Step 3: methyl 5,6-dihydro-4H-thieno[2,3-c]pyrrole-2-carboxylate

To a mixture of methyl5-[(2-nitrophenypsulfonyl]-5,6-dihydro-4H-thieno[2,3-c]pyrrole-2-carboxylate(3.297 g, 8.95 mmol) and cesium carbonate (5.6 g, 17 mmol) inacetonitrile (95 mL) was added a solution of benzenethiol (1.8 mL, 17mmol) in acetonitrile (20 mL). The resulting reaction mixture wasstirred at room temperature for 4 hours. The solvent was removed invacuo and the residue was washed exhaustively with Et₂O to afford an offwhite solid (1.326 g, 80%). LCMS (FA) ES+ 184; ¹H NMR (400 MHz, MeOD) δ7.59 (s, 1H), 4.32 (t, J=2.0 Hz, 2H), 4.17 (t, J=2.0 Hz, 2H), 3.85 (s,3H).

Example 102 Synthesis of5-(2,2-dimethylpropanoyl)-N-hydroxy-5,6-dihydro-4H-thieno[2,3-c]pyrrole-2-carboxamide(Compound 223)

Step 1: methyl5-pivaloyl-5,6-dihydro-4H-thieno[2,3-c]pyrrole-2-carboxylate

To a mixture of methyl 5,6-dihydro-4H-thieno[2,3-c]pyrrole-2-carboxylate(0.023 g, 0.127 mmol) and pivalic acid (0.014 g, 0.14 mmol) in methylenechloride (0.92 mL) was addedN,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uroniumhexafluorophosphate (0.055 g, 0.146 mmol) and N-methylmorpholine (0.035mL, 0.32 mmol) respectively. The reaction mixture was stirred at roomtemperature overnight. The reaction was diluted with additional DCM (2mL) and washed with saturated aqueous NaHCO₃ (2 mL). The aqueous layerwas extracted with additional DCM (3 mL), and the combined organiclayers were concentrated to afford an oily residue. LCMS (FA) ES+ 268.

Step 2:5-(2,2-dimethylpropanoyl)-N-hydroxy-5,6-dihydro-4H-thieno[2,3-c]pyrrole-2-carboxamide

The residue obtained in the previous step was taken up in methanol (1.7mL, 43 mmol) and to the solution was added hydroxylamine hydrochloride(0.035 g, 0.51 mmol) and potassium hydroxide (0.086 g, 1.5 mmol). Themixture was heated at 80° C. for 45 minutes. The reaction was cooled toroom temperature and the solvent evaporated to dryness. The material wasdissolved in DMSO (1 mL), the insolubles removed via filtration andpurified by Gilson prep-HPLC. Lyophilization of fractions containing thedesired product afforded the title compound as a white solid (6.1 mg,33% over two steps). LCMS (FA) ES+ 267; ¹H NMR (400 MHz, DMSO) δ 11.24(s, 1H), 9.14 (s, 1H), 7.43 (s, 1H), 4.74 (dd, J=137.5, 64.7 Hz, 4H),1.22 (s, 9H).

Example 103

The following compounds were prepared in a fashion analogous to Example102 starting from the intermediates which were prepared as describedabove and the corresponding carboxylic acids.

LC-MS Compound Structure (FA) 230

ES+ 347 231

ES+ 345

Example 104

The following compound was prepared in a fashion analogous to thatdescribed in Example 99 starting from the intermediate prepared asdescribed in Example 2 employing the corresponding carboxylic acid.

Com- LC-MS pound Structure (FA) 159

ES+ 308

Example 105 Synthesis of5-(4-chlorobenzoyl)-N-hydroxy-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxamide(Compound 240)

Step 1: ethyl5-(4-chlorobenzoyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxylate

To ethyl 4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxylate (0.237 g,1.12 mmol), 4-chlorobenzoic acid (0.228 g, 1.46 mmol) inN,N-dimethylformamide (6 mL) was added a solution offluoro-N,N,N′,N′-tetramethylformamidinium hexafluorophosphate (0.444 g,1.68 mmol) in N,N-diisopropylethylamine (0.6 mL). The reaction solutionwas then stirred overnight at room temperature. Water was then added andthe mixture was extracted into ethyl acetate. The organic layer waswashed with brine and evaporated. Purification of the residue obtainedon silica gel (0-10% ethyl acetate/DCM) afforded a sticky white solid(208 mg, 53%). LCMS (FA) ES+ 350.

Step 2:5-(4-chlorobenzoyl)-N-hydroxy-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxamide

A mixture of hydroxylamine hydrochloride (2 g, 29 mmol) in methanol (10mL) was heated at 90° C. under a dry nitrogen atmosphere untilhomogenous. To the heated solution was added a solution of potassiumhydroxide (2.85 g, 50.8 mmol) in methanol (6 mL). The formation of awhite precipitate was observed. After heating at 90° C. for 30 minutes,the mixture was cooled to room temperature and the solids allowed tosettle. The resulting solution was assumed to have a 1.7 M concentrationof hydroxylamine•potassium salt and was carefully removed by syringe toexclude solids. An aliquot of the above solution (3.5 mL 5.92 mmol) wasadded to a solution of ethyl5-(4-chlorobenzoyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxylateobtained in the previous step dissolved in methanol (3.5 mL). Afterstirring for 30 minutes at room temperature, the reaction was quenchedwith the addition of acetic acid (0.3 mL, 5.86 mmol). The reactionmixture was concentrated to dryness and purified on a BioCAD 700E HPLCinstrument using Sunfire C-18 (18×150 mm) column to afford a white solid(115 mg, 58%). LCMS (FA) ES+ 337; ¹H NMR (400 MHz, MeOD) δ 7.55-7.41 (m,4H), 7.36 (br s, 0.5H), 7.13 (br s, 0.5H), 4.75 (br s, 1H), 4.52 (br s,1H), 4.05 (br s, 1H), 3.70 (br s, 1H), 2.95 (br s, 2H).

Example 106 HDAC6 Enzyme Assay

To measure the inhibition of HDAC6 activity, purified human HDAC6 (BPSBioscience; Cat. No. 5006) is incubated with substrateAc-Arg-Gly-Lys(Ac)-AMC peptide (Bachem Biosciences; Cat. No. I-1925) for1 hour at 30° C. in the presence of test compounds or vehicle DMSOcontrol. The reaction is stopped with the HDAC inhibitor trichostatin A(Sigma; Cat. No. T8552) and the amount of Arg-Gly-Lys-AMC generated isquantitated by digestion with trypsin (Sigma; Cat. No. T1426) andsubsequent measurement of the amount of AMC released using a fluorescentplate reader (Pherastar; BMG Technologies) set at Ex 340 nm and Em 460nm. Concentration response curves are generated by calculating thefluorescence increase in test compound-treated samples relative toDMSO-treated controls, and enzyme inhibition (IC₅₀) values aredetermined from those curves.

Example 107 Nuclear Extract HDAC Assay

As a screen against Class I HDAC enzymes, HeLa nuclear extract (BIOMOL;Cat. No. KI-140) is incubated with Ac-Arg-Gly-Lys(Ac)-AMC peptide(Bachem Biosciences; Cat. No. 1-1925) in the presence of test compoundsor vehicle DMSO control. The Hela nuclear extract is enriched for ClassI enzymes HDAC1, -2 and -3. The reaction is stopped with the HDACinhibitor Trichostatin A (Sigma; Cat. No. T8552) and the amount ofArg-Gly-Lys-AMC generated is quantitated by digestion with trypsin(Sigma; Cat. No. T1426) and subsequent measurement of the amount of AMCreleased using a fluorescent plate reader (Pherastar; BMG Technologies)set at Ex 340 nm and Em 460 nm. Concentration response curves aregenerated by calculating the fluorescence increase in testcompound-treated samples relative to DMSO-treated controls, and enzymeinhibition (IC₅₀) values are determined from those curves.

Example 108 Western Blot and Immunofluorescence Assays

Cellular potency and selectivity of compounds are determined using apublished assay (Haggarty et al., Proc. Natl. Acad. Sci. USA 2003, 100(8): 4389-4394) using Hela cells (ATCC cat#CCL-2™) which are maintainedin MEM medium (Invitrogen) supplemented with 10% FBS; or multiplemyeloma cells RPMI-8226 (ATCC cat# CCL-155™) which are maintained inRPMI 1640 medium (Invitrogen) supplemented with 10% FBS. Briefly, cellsare treated with inhibitors for 6 or 24 h and either lysed for Westernblotting, or fixed for immunofluorescence analyses. HDAC6 potency isdetermined by measuring K40 hyperacetylation of alpha-tubulin with anacetylation selective monoclonal antibody (Sigma cat# T7451) in IC50experiments. Selectivity against Class I HDAC activity is determinedsimilarly using an antibody that recognizes hyperacetylation of histoneH4 (Upstate cat #06-866) in the Western blotting assay or nuclearacetylation (Abcam cat# ab21623) in the immunofluorescence assay.

Example 109 In vivo Tumor Efficacy Model

Female NCr-Nude mice (age 6-8 weeks, Charles River Labs) are asepticallyinjected into the subcutaneous space in the right dorsal flank with1.0-5.0×10⁶ cells (SKOV-3, HCT-116, BxPC3) in 100 of a 1:1 ratio ofserum-free culture media (Sigma Aldrich) and BD Matrigel™ (BDBiosciences) using a 1 mL 26⅜ gauge needle (Becton DickinsonRef#309625). Alternatively, some xenograft models require the use ofmore immunocompromised strains of mice such as CB-17 SCID (Charles RiverLabs) or NOD-SCID (Jackson Laboratory). Furthermore, some xenograftmodels require serial passaging of tumor fragments in which smallfragments of tumor tissue (approximately 1 mm³) are implantedsubcutaneously in the right dorsal flank of anesthetized (3-5%isoflourane/oxygen mixture) NCr-Nude, CB-17 SCID or NOD-SCID mice (age5-8 weeks, Charles River Labs or Jackson Laboratory) via a 13-ga trocarneedle (Popper & Sons 7927). Tumor volume is monitored twice weekly withVernier calipers. The mean tumor volume is calculated using the formulaV=W²×L/2. When the mean tumor volume is approximately 200 mm³, theanimals are randomized into treatment groups of ten animals each. Drugtreatment typically includes the test compound as a single agent, andmay include combinations of the test compound and other anticanceragents. Dosing and schedules are determined for each experiment based onprevious results obtained from pharmacokinetic/pharmacodynamic andmaximum tolerated dose studies. The control group will receive vehiclewithout any drug. Typically, test compound (100-200 μL) is administeredvia intravenous (27-ga needle), oral (20-ga gavage needle) orsubcutaneous (27-ga needle) routes at various doses and schedules. Tumorsize and body weight are measured twice a week and the study isterminated when the control tumors reach approximately 2000 mm³, and/orif tumor volume exceeds 10% of the animal body weight or if the bodyweight loss exceeds 20%.

The differences in tumor growth trends over time between pairs oftreatment groups are assessed using linear mixed effects regressionmodels. These models account for the fact that each animal is measuredat multiple time points. A separate model is fit for each comparison,and the areas under the curve (AUC) for each treatment group arecalculated using the predicted values from the model. The percentdecrease in AUC (dAUC) relative to the reference group is thencalculated. A statistically significant P value suggests that the trendsover time for the two treatment groups are different.

The tumor measurements observed on a date pre-specified by theresearcher (typically the last day of treatment) are analyzed to assesstumor growth inhibition. For this analysis, a T/C ratio is calculatedfor each animal by dividing the tumor measurement for the given animalby the mean tumor measurement across all control animals. The T/C ratiosacross a treatment group are compared to the T/C ratios of the controlgroup using a two-tailed Welch's t-test. To adjust for multiplicity, aFalse Discovery Rate (FDR) is calculated for each comparison using theapproach described by Benjamini and Hochberg, J. R. Stat. Soc. B 1995,57:289-300.

As detailed above, compounds of the invention inhibit HDAC6. In certainembodiments, compounds of the invention inhibit HDAC6 with an IC50 valueof less than 50 nM including compounds: 1, 2, 3, 4, 5, 6, 7, 8, 11, 13,14, 16, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 30, 31, 32, 33, 34,40, 42, 51, 54, 64, 65, 67, 68, 76, 80, 88, 89, 94, 95, 98, 99, 103,107, 116, 127, 131, 132, 133, 139, 140, 146, 152, 156, 159, 163, 169,171, 176, 177, 179, 184, 186, 187, 188, 193, 194, 205, 209, 212, 231,233.

In certain embodiments, compounds of the invention inhibit HDAC6 with anIC50 value of greater than 50 nM and less than 100 nM includingcompounds: 9, 10, 15, 29, 47, 48, 52, 62, 75, 81, 100, 125, 149, 178,182, 199, 216, 221, 225, 230.

In certain embodiments, compounds of the invention inhibit HDAC6 with anIC50 value of greater than 100 nM and less than 1 μM includingcompounds: 36, 69, 93, 106, 189, 191, 197, 200, 201, 202, 203, 204, 206,207, 208, 211, 213, 215, 217, 219, 223, 226, 227, 228, 229, 232.

In certain embodiments, compounds of the invention inhibit HDAC6 with anIC50 value of greater than 1 μM including compounds: 12, 17, 56, 111,190, 192, 195, 196, 198, 210, 214, 218, 220, 222, 224, 234.

As detailed above, compounds of the invention are selective for HDAC6over other Class I HDAC enzymes. In some embodiments, the ratio of HDACIC50 (as obtained in the nuclear extract assay described above) to HDAC6IC50 is 10:1. In certain embodiments, the ratio of HDAC IC50 to HDAC6IC50 is 100:1. In certain embodiments, the ratio of HDAC IC50 to HDAC6IC50 is 1000:1.

While we have described a number of embodiments of this invention, it isapparent that our basic examples may be altered to provide otherembodiments, which utilize the compounds and methods of this invention.Therefore, it will be appreciated that the scope of this invention is tobe defined by the appended claims rather than by the specificembodiments, which have been represented by way of examples.

What is claimed is:
 1. A compound of formula (I):

or a pharmaceutically acceptable salt thereof; wherein: p is 1, q is 1;or p is 0, q is 2; G is —R³, —V₁—R³, —V₁-L₁-R³, -L₁-V₂—R³, -L₁-R³, or-L₁-V₂-L₂-R³; L₁and L₂are each independently unsubstituted orsubstituted C₁₋₃ alkylene, where one carbon atom may be replaced with—CR^(A)═CR^(A)—; V₁ is —C(O)—, —C(S)—, —C(O)—N(R^(4a))—, —C(O)—O—, or—S(O)₂—; V₂ is —C(O)—, —C(S)—, —N(R^(4a))—, —C(O)—N(R^(4a))—,—N(R^(4a))—C(O)—, —SO₂—N(R^(4a))—, —N(R^(4a))—SO₂—, —C(O)—O—, —O—C(O)—,—O—, —S—, —S(O)—, —S(O)₂—, —N(R^(4a))—C(O)—N(R^(4a))—,—N(R^(4a))—C(O)—O—, —O—C(O)—N(R^(4a))—, or —N(R^(4a))—SO₂—N(R^(4a))—; R³is unsubstituted or substituted C₁₋₆ aliphatic, unsubstituted orsubstituted 3-10-membered cycloaliphatic, unsubstituted or substituted4-10-membered heterocyclyl having 1-4 heteroatoms independently selectedfrom nitrogen, oxygen, and sulfur, unsubstituted or substituted6-10-membered aryl, or unsubstituted or substituted 5-10-memberedheteroaryl having 1-5 heteroatoms independently selected from nitrogen,oxygen, and sulfur; each occurrence of R^(A) is independently hydrogen,halo, or unsubstituted or substituted C₁₋₄ aliphatic; each occurrence ofR^(4a) is independently hydrogen, or unsubstituted or substituted C₁₋₄aliphatic; R¹ is hydrogen, halo, —CN, C₁₋₃ alkyl, C₁₋₃haloalkyl, —O—C₁₋₃alkyl, —O—C₁₋₃ haloalkyl, —NHC(O)C₁₋₃ alkyl, —NHC(O)NHC₁₋₃ alkyl, orNHS(O)₂C₁₋₃ alkyl; ring A is optionally further substituted with noccurrences of R²; each occurrence of R² is independently halo, C₁₋₄aliphatic, —CN, —OR^(B), —SR^(C), —N(R^(B))₂, —NR^(B)C(O)R^(B),—NR^(B)C(O)N(R^(B))₂, —NR^(B)CO₂R^(C), —CO₂R^(B), —C(O)R^(B),—C(O)N(R^(B))₂, —OC(O)N(R^(B))₂, —S(O)₂R^(C), —SO₂N(R^(B))₂, —S(O)R^(C),—NR^(B)SO₂N(R^(B))₂, —NR^(B)SO₂R^(C), or a C₁₋₄ aliphatic substitutedwith R^(D), halo, —CN, —OR^(B), —SR^(C), —N(R^(B))₂, —NR^(B)C(O)R^(B),—NR^(B)C(O)_(N)(R^(B))₂, —NR^(B)CO₂R^(C), —CO₂R^(B), —C(O)R^(B),—C(O)N(R^(B))₂, —OC(O)N(R^(B))₂, —S(O)₂R^(C), —SO₂N(R^(B))₂, —S(O)R^(C),—NR^(B)SO₂N(R^(B))₂, or —NR^(B)SO₂R^(C); or two R² are taken together toform a 3-6 membered cycloaliphatic ring; each occurrence of R^(B) isindependently H or C₁₋₄ aliphatic; or two R^(B) on the same nitrogenatom taken together with the nitrogen atom form a 5-8 membered aromaticor non-aromatic ring having in addition to the nitrogen atom 0-2 ringheteroatoms selected from N, O and S; each occurrence of R^(C) isindependently C₁₋₄ aliphatic; each occurrence of R^(D) is independently6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatomsindependently selected from nitrogen, oxygen, or sulfur; and n is 0-4.2. A compound of formula (I):

or a pharmaceutically acceptable salt thereof; wherein: p is 1, q is 1;or p is 0, q is 2; G is —R³, —V₁—R³, —V₁-L₁-R³, -L₁-V₁—R³, -L₂-V₂—R³,—V₁-L₁-V₂—R³, or -L₁-R³—, L₁ is unsubstituted or substituted C₁₋₃alkylene chain, where one carbon atom may be replaced with—CR^(A)═CR^(A)—; L₂ is unsubstituted or substituted C₂₋₃ alkylene chain,where one carbon atom may be replaced with —CR^(A)═CR^(A)—; V₁ is—C(O)—, —C(S)—, —C(O)—N(R^(4a))—, —C(O)—O—, or —S(O)₂—; V₂ is —C(O)—,—C(S)—, —N(R^(4a))—, —C(O)—N(R^(4a))—, —N(R^(4a))—C(O)—,—SO₂—N(R^(4a))—, —N(R^(4a))—SO₂—, —C(O)—O—, —O—C(O)—,—O—, —S—, —S(O)—,—S(O)₂—, —N(R^(4a))—C(O)—N(R^(4a))—, —N(R^(4a))—C(O)—O—,—O—C(O)—N(R^(4a))—, or —N(R^(4a))—SO₂—N(R^(4a))—; R³ is unsubstituted orsubstituted C₁₋₆ aliphatic, unsubstituted or substituted 3-10-memberedcycloaliphatic, unsubstituted or substituted 4-10-membered heterocyclylhaving 1-4 heteroatoms independently selected from nitrogen, oxygen, andsulfur, unsubstituted or substituted 6-10-membered aryl, orunsubstituted or substituted 5-10-membered heteroaryl having 1-4heteroatoms independently selected from nitrogen, oxygen, and sulfur;each occurrence of R^(A) is independently hydrogen, halo, orunsubstituted or substituted C₁₋₄ aliphatic; each occurrence of R^(4a)is independently hydrogen, or unsubstituted substituted C₁₋₄ aliphaticgroup; R^(l) is hydrogen, chloro, fluoro, —O—C₁₋₄ alkyl, or C₁₋₄fluoroalkyl; ring A is optionally further substituted with n occurrencesof R²; each occurrences of R² is independently fluoro, C₁₋₄ alkyl, C₁₋₄haloalkyl, or R^(D); or two R² are taken together to form a 3-6 memberedcycloaliphatic ring; each occurrence of R^(D) is independentlyunsubstituted 6-10-membered aryl, or unsubstituted or substituted5-10-membered heteroaryl having 1-5 heteroatoms independently selectedfrom nitrogen, oxygen, and sulfur; and n is 0-4.
 3. The compound ofclaim 2, wherein: R¹is hydrogen or methyl; each occurrence of R² isindependently fluoro, methyl, or trifluoromethyl; V₁ is —C(O)—,—C(O)—N(R^(4a)), or —S(O)₂—; V₂ is —C(O)—, —N(R^(4a))—,—C(O)—N(R^(4a))', —N(R^(4a))—C(O)—, —SO₂—N(R^(4a))—, —N(R^(4a))—O—, or—S—; and n is 0-2.
 4. The compound of claim 2, represented by formulas(II-A)-(II-B):


5. The compound of claim 2, wherein: R³ when substituted is substitutedwith 1-4 independent occurrences of —R⁵, wherein R⁵ is —R^(5a), —R^(5d),-L₃-R^(5d), or -V₃-L₃-R^(5d); each occurrence of R^(5a) is independentlyhalogen, C₁₋₄ aliphatic, —CN, —NO₂, —N(R^(5b))₂, —OR^(5b), —SR^(5c),—S(O)₂R^(5c), —S(O)R^(5c)—C(O)R^(5b), —C(O)OR^(5b), —C(O)N(R^(5b))₂,—S(O)₂N(R^(5b))₂, —OC(O)N(R^(5b))₂, —N(R^(5e))C(O)R^(5b),—N(R^(5e))SO₂R^(5c), —N(R^(5e))C(O)OR^(5b), —N(R^(5e))C(O)N(R^(5b))₂, or—N(R^(5e))SO₂N(R^(5b))₂, or a C₁₋₄ aliphatic substituted with R^(5dd),halogen, —CN, —NO₂, —N(R^(5b))₂, —OR^(5b), —SR^(5c), —S(O)₂R^(5c),—S(O)R^(5c)—C(O)R^(5b), —C(O)OR^(5b), —C(O)N(R^(5b))₂, —S(O)₂N(R^(5b))₂,—OC(O)N(R^(5b))₂, —N(R^(5e))C(O)R^(5b), —N(R^(5e))SO₂R^(5c),—N(R^(5e))C(O)OR^(5b), —N(R^(5e))C(O)N(R^(5b))₂, or—N(R^(5e))SO₂N(R^(5b))₂; each occurrence of R^(5b) is independentlyhydrogen or an optionally substituted group selected from C₁₋₆aliphatic, 3-10-membered cycloaliphatic, 4-10-membered heterocyclylhaving 1-4 heteroatoms independently selected from nitrogen, oxygen, andsulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5heteroatoms independently selected from nitrogen, oxygen, and sulfur; ortwo occurrences of R^(5b) on the same nitrogen atom can be takentogether with the nitrogen atom to which they are bound to form anoptionally substituted 4-7-membered heterocyclyl ring having 0-1additional heteroatoms selected from nitrogen, oxygen, and sulfur; eachoccurrence of R^(5c) is independently an optionally substituted groupselected from C₁₋₆ aliphatic, 3-10-membered cycloaliphatic,4-10-membered heterocyclyl having 1-4 heteroatoms independently selectedfrom nitrogen, oxygen, and sulfur, 6-10-membered aryl, or 5-10-memberedheteroaryl having 1-5 heteroatoms independently selected from nitrogen,oxygen, and sulfur; each occurrence of R^(5d) is an optionallysubstituted group selected from 6-10-membered aryl, or 5-10-memberedheteroaryl having 1-5 heteroatoms independently selected from nitrogen,oxygen, and sulfur; each occurrence of R^(5dd) is an optionallysubstituted group selected from 6-10-membered aryl, or 5-10-memberedheteroaryl having 1-5 heteroatoms independently selected from nitrogen,oxygen, and sulfur; each occurrence of R^(5e) is independently hydrogenor an optionally substituted C₁₋₆ aliphatic group; each occurrence of V₃is independently —N(R^(5e)), —O—, —S—, —S(O)—, —S(O)₂—, —C(O)—, —C(O)O—,—C(O)N(R^(5e))—, —S(O)₂N(R^(5e))—, —OC(O)N(R^(5e))—, —N(R^(5e))C(O)—,—N(R^(5e))SO₂—, —N(R^(5e))C(O)O—, —N(R^(5e))C(O)N(R^(5e))—,—N(R^(5e))SO₂N(R^(5e))—, —OC(O)—, or —C(O)N(R^(5e))O—; and L₃ is anoptionally substituted C₁₋₃ alkylene chain, where one carbon atom may bereplaced with —CR^(A)═CR^(A)—.
 6. The compound of claim 5, wherein: G is—R³, —C(R⁶)(R^(6′))—R³, —C(O)—R³, or —S(O)₂—R³; R⁶ is hydrogen, C₁₋₄aliphatic, C₃₋₆ cycloaliphatic, or 6-10-membered aryl; R^(6′) ishydrogen, C₁₋₄ aliphatic, C₃₋₆ cycloaliphatic, or 6-10-membered aryl; orR⁶ and R^(6′) are taken together to form a C₃₋₆ cycloaliphatic group; R³is —R^(3a); and R^(3a) is unsubstituted or substituted 6-10-memberedaryl, or unsubstituted or substituted 5-10-membered heteroaryl having1-5 heteroatoms independently selected from nitrogen, oxygen, andsulfur, wherein R^(3a) if substituted is substituted with 0-1occurrences of —R^(5a), and one occurrence of —R^(5d).
 7. The compoundof claim 6, represented by formulas (II-A)-(II-B):

wherein: R¹ is hydrogen, chloro, fluoro, methoxy, cyano, or methyl; eachoccurrence of R² is independently fluoro, methyl, or trifluoromethyl; nis 0-2; R^(5a) is chloro, fluoro, C₁₋₄ alkyl, C₁₋₆ fluoroalkyl, —O—C₁₋₆alkyl, —O—C₁₋₆ fluoroalkyl, cyano, hydroxy, —NHC(O)C₁₋₆ alkyl, —NHC₁₋₆alkyl, —N(C₁₋₆ alkyl)₂, —C(O)NHC₁₋₆ alkyl, —C(O)N(C₁₋₆ alkyl)₂,—NHC(O)NHC₁₋₆ alkyl, —NHC(O)N(C₁₋₆alkyl)₂, or —NHS(O)₂C₁₋₆ alkyl; R^(5d)if substituted is substituted with 0-2 occurrences of —R^(7a); and eachoccurrence of R^(7a) is independently chloro, fluoro, bromo, iodo, C₁₋₆alkyl, C₁₋₆ fluoroalkyl, —O—C₁₋₆ alkyl, —O—C₁₋₆ fluoroalkyl, cyano,hydroxy, —NHC(O)C₁₋₆ alkyl, —NHC₁₋₆ alkyl, —N(C₁₋₆ alkyl)₂, —C(O)NHC₁₋₆alkyl, —C(O)N(C₁₋₆ alkyl)₂, —NHC(O)NHC₁₋₆ alkyl, —NHC(O)N(C₁₋₆ alkyl)₂,or —NHS(O)₂C₁₋₆ alkyl.
 8. The compound of claim 7, wherein: R¹ ishydrogen or methyl; and n is
 0. 9. The compound of claim 7, wherein:R^(5d) is thienyl, pyrrolyl, pyrazolyl, isoxazolyl, triazolyl, phenyl,pyridyl, pyrimidinyl, or benzothienyl.
 10. The compound of claim 5,wherein: G is —[C(R⁶)(R^(6′))]_(z)—R³, —C(O)—[C(R⁶)(R^(6′))]_(z)—R³,—C(O)—NH—[C(R⁶)(R^(6′))]_(z)—R³, —S(O)₂—[C(R⁶)(R^(6′))]_(z)—R³,—[C(R⁶)(R^(6′))]_(y)—V_(2a)—R³, —C(O)—[C(R⁶)(R^(6′))]_(y)—V_(2a)—R³,—C(R⁶)(R^(6′))—V_(2a′)—R³, or —C(O)—C(R⁶)(R^(6′))—V_(2a′)—R³; R⁶ ishydrogen, C₁₋₄ aliphatic, C₃₋₆ cycloaliphatic, or 6-10-membered aryl;R^(6′) is hydrogen, C₁₋₄ aliphatic, C₃₋₆ cycloaliphatic, or6-10-membered aryl; or R⁶ and R^(6′) are taken together to form a C₃₋₆cycloaliphatic group; V_(2a) is —C(O)—, —O—, —S—, —N(R^(4a))—, or—C(O)N(R^(4a))—; V_(2a)′ is —O—, —S—, or —N(R^(4a))—; R³ is —R^(3d);R^(3d) is unsubstituted or substituted C₁₋₆ aliphatic, unsubstituted orsubstituted 3-10-membered cycloaliphatic, unsubstituted or substituted4-10-membered heterocyclyl having 1-4 heteroatoms independently selectedfrom nitrogen, oxygen, and sulfur, unsubstituted or substituted6-10-membered aryl, or unsubstituted or substituted 5-10-memberedheteroaryl having 1-5 heteroatoms independently selected from nitrogen,oxygen, and sulfur, wherein R^(3d) if substituted is substituted with0-2 independent occurrences of —R^(5a); z is 0-3; and y is 1-2.
 11. Thecompound of claim 10, represented by formula (II-A)-(II-B):

wherein: R¹ is hydrogen, chloro, fluoro, methoxy, cyano, or methyl; eachoccurrence of R² is independently fluoro, methyl, or trifluoromethyl; nis 0-2; R^(3d) is unsubstituted or substituted with 0-1 occurrences of—R^(5a); and R^(5a) is chloro, fluoro, C₁₋₄ alkyl, C₁₋₆ fluoroalkyl,—O—C₁₋₆ alkyl, —O—C₁₋₆ fluoroalkyl, cyano, hydroxy, —NHC(O)C₁₋₆ alkyl,—NHC₁₋₆ alkyl, —N(C₁₋₆ alkyl)₂, —C(O)NHC₁₋₆ alkyl, —C(O)N(C₁₋₆ alkyl)₂,—NHC(O)NHC₁₋₆ alkyl, —NHC(O)N(C₁₋₆ alkyl)₂, or —NHS(O)₂C₁₋₆ alkyl. 12.The compound of claim 11, wherein: R¹ is hydrogen or methyl; and n is 0.13. The compound of claim 11, wherein: R^(5a) is chloro, fluoro, methyl,ethyl, trifluoromethyl, methoxy, ethoxy, trifluoromethoxy, cyano, orhydroxy.
 14. The compound of claim 11, wherein: G is—[C(R⁶)(R^(6′))]_(z)—R³, —C(O)—[C(R⁶)(R^(6′))]_(z)—R³, or—S(O)₂—[C(R⁶)(R^(6′))]_(z)—R³.
 15. The compound of claim 2, wherein thecompound is: 16-(2,2-dimethylpropanoyl)-N-hydroxy-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide,26-(cyclohexylcarbonyl)-N-hydroxy-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide,3N-hydroxy-6-[(1-methylcyclohexyl)carbonyl]-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide,46-[2-(4-chlorophenyl)-2-methylpropanoyl]-N-hydroxy-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide, 5N-hydroxy-6-(3-thienylcarbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide,6N-hydroxy-6-(2-phenoxybutanoyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide,76-[(5-chloro-4-methoxy-3-thienyl)carbonyl]-N-hydroxy-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide, 8N-hydroxy-6-(4,5,6,7-tetrahydro-2H-indazol-3-ylcarbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide, 96-(2,2-diphenylbutanoyl)-N-hydroxy-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide,106-(dicyclohexylacetyl)-N-hydroxy-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide,11N-hydroxy-6-{[2-methyl-4-(trifluoromethyl)-1,3-thiazol-5-yl]carbonyl}-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide, 126-[(2,4-dimethylphenoxy)acetyl]-N-hydroxy-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide,136-{[1-(2-chloro-4-fluorophenyl)cyclopentyl]carbonyl}-N-hydroxy-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide, 146-[1-adamantylcarbonyl]-N-hydroxy-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide,15N-hydroxy-6-{[1-(phenylsulfonyl)piperidin-2-yl]carbonyl}-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide, 16N-hydroxy-6-[2-methyl-5-(piperidin-1-ylsulfonyl)-3-furoyl]-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide, 176-(9H-fluoren-9-ylacetyl)-N-hydroxy-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide,186-[(2,2-diphenylethyl)sulfonyl]-N-hydroxy-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide,196-(butylsulfonyl)-N-hydroxy-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide,206-[(3,5-dimethylisoxazol-4-yl)sulfonyl]-N-hydroxy-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide, 21N-hydroxy-6-{[4-(trifluoromethyl)phenyl]sulfonyl}-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide, 226-(3,4-dihydro-2H-1,5-benzodioxepin-7-ylmethyl)-N-hydroxy-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide, 23N-hydroxy-6-[4-(1H-pyrazol-1-yl)benzyl]-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide,24N-hydroxy-6-[(5-methyl-2-phenyl-2H-1,2,3-triazol-4-yl)methyl]-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide, 256-(2,1,3-benzothiadiazol-4-ylmethyl)-N-hydroxy-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide, 265-(2,2-dimethylpropanoyl)-N-hydroxy-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxamide,27N-hydroxy-5-[(1-methyl-1H-pyrrol-2-yl)carbonyl]-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxamide, 28N-hydroxy-5-[(1-methylcyclohexyl)carbonyl]-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxamide,29N-hydroxy-5-[(5-methylpyrazin-2-yl)carbonyl]-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxamide,30N-hydroxy-5-(quinolin-8-ylcarbonyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxamide,315-(cyclohexylcarbonyl)-N-hydroxy-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxamide,325-[4-(4,6-dimethoxypyrimidin-2-yl)benzoyl]-N-hydroxy-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxamide, 335-(1-adamantylcarbonyl)-N-hydroxy-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxamide,34N-hydroxy-5-{[4-(trifluoromethyl)phenyl]sulfonyl}-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxamide, 355-[3-(2,3-dihydro-1H-indol-1-yl)-3-oxopropyl]-N-hydroxy-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxamide, 366-[3,5-bis(trifluoromethyl)benzoyl]-N-hydroxy-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide,37N-hydroxy-5-[3-(trifluoromethoxy)benzyl]-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxamide,38N-hydroxy-5-[(5-methoxy-1-methyl-1H-indol-2-yl)carbonyl]-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxamide, 395-({5-[(cyclopropylcarbonyl)amino]-1-methyl-1H-indo1-2-yl}carbonyl)-N-hydroxy-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxamide, 40N²-hydroxy-N⁶-(5-phenyl-2-thienyl)-4,7-dihydrothieno[2,3-c]pyridine-2,6(5H)-dicarboxamide,41N-hydroxy-6-{5-[4-(trifluoromethyl)phenyl]-1,3-thiazol-2-yl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide, 426-(2-furoyl)-N-hydroxy-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide,43N-hydroxy-5-{[5-(2-methoxyphenyl)-1,2,4-oxadiazol-3-yl]methyl}-3-methyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxamide, 446-[2-(benzylamino)pyrimidin-4-yl]-N-hydroxy-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide,45N⁵-[4-chloro-3-(trifluoromethyl)phenyl]-N²-hydroxy-6,7-dihydrothieno[3,2-c]pyridine-2,5(4H)-dicarboxamide, 465-[5-(3-chlorophenyl)-1,3-thiazol-2-yl]-N-hydroxy-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxamide, 476-[(2,4-dimethyl-1,3-thiazol-5-yl)acetyl]-N-hydroxy-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide, 48N-hydroxy-6-[(2-methyl-4-phenylpyrimidin-5-yl)carbonyl]-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide, or 49N-hydroxy-4-methyl-6-[4-(trifluoromethyl)benzyl]-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide.


16. The compound of claim 2, wherein the compound is: 516-(4-fluoro-3-methylbenzoyl)-N-hydroxy-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide,526-[(3,5-difluorophenyl)acetyl]-N-hydroxy-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide,53N-hydroxy-5-[5-(4-methoxyphenyl)-1,3-thiazol-2-yl]-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxamide, 54N²-hydroxy-N⁶-[3-(trifluoromethyl)phenyl]-4,7-dihydrothieno[2,3-c]pyridine-2,6(5H)-dicarboxamide,55N²-hydroxy-N⁵-(3-methoxybenzyl)-6,7-dihydrothieno[3,2-c]pyridine-2,5(4H)-dicarboxamide,566-({3-[(2-amino-2-oxoethyl)sulfanyl]-2-thienyl}carbonyl)-N-hydroxy-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide, 576-[2-(4-chlorophenoxy)ethyl]-N-hydroxy-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide,586-({5-[(cyclopropylcarbonyl)amino]-1-methyl-1H-indol-2-yl}carbonyl)-N-hydroxy-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide, 59N-hydroxy-6-(5-pyridin-4-yl-1,3-thiazol-2-yl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide,60N⁵-(4-chlorobenzyl)-N²-hydroxy-6,7-dihydrothieno[3,2-c]pyridine-2,5(4H)-dicarboxamide,61N⁵-[(1S)-1-(4-chlorophenyl)ethyl]-N²-hydroxy-6,7-dihydrothieno[3,2-c]pyridine-2,5(4H)-dicarboxamide 626-[(3,5-dimethylisoxazol-4-yl)acetyl]-N-hydroxy-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide, 63N²-hydroxy-N⁶-(4-methoxybenzyl)-4,7-dihydrothieno[2,3-c]pyridine-2,6(5H)-dicarboxamide,646-(4-tert-butylbenzoyl)-N-hydroxy-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide,65N-hydroxy-6-[(5-methyl-2-phenyl-1,3-oxazol-4-yl)acetyl]-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide, 665-{[2-(4-chloro-2-methoxyphenyl)-4-methyl-4H-furo[3,2-b]pyrrol-5-yl]carbonyl}-N-hydroxy-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxamide, 676-(5-tert-butyl-2-methyl-3-furoyl)-N-hydroxy-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide,68N-hydroxy-3-methyl-5-[4-(trifluoromethyl)benzyl]-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxamide, 696-[(1-tert-butyl-3-methyl-1H-pyrazol-5-yl)carbonyl]-N-hydroxy-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide, 70N-hydroxy-5-(quinolin-2-ylmethyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxamide,716-[(4'-fluorobiphenyl-3-yl)sulfonyl]-N-hydroxy-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide,726-[(1-cyclopropyl-1H-pyrrol-2-yl)carbonyl]-N-hydroxy-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide, 73N-hydroxy-5-(5-pyridin-4-yl-1,3-thiazol-2-yl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxamide,74N⁵-[2-fluoro-5-(trifluoromethyl)phenyl]-N²-hydroxy-6,7-dihydrothieno[3,2-c]pyridine-2,5(4H)-dicarboxamide, 75N-hydroxy-6-[(2-methyl-1,3-thiazol-4-yl)acetyl]-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide,76N⁶-cyclohexyl-N²-hydroxy-4,7-dihydrothieno[2,3-c]pyridine-2,6(5H)-dicarboxamide,77N-hydroxy-6-[3-(trifluoromethoxy)benzyl]-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide,785-[(1-cyclopropyl-1H-pyrrol-2-yl)carbonyl]-N-hydroxy-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxamide, 79N²-hydroxy-N⁶-(3-methoxybenzyl)-4,7-dihydrothieno[2,3-c]pyridine-2,6(5H)-dicarboxamide,80N²-hydroxy-N⁶-(3-methylphenyl)-4,7-dihydrothieno[2,3-c]pyridine-2,6(5H)-dicarboxamide,81N-hydroxy-6-[(6-hydroxypyridin-2-yl)carbonyl]-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide,825-[(4,5-dichloro-1-methyl-1H-pyrrol-2-yl)carbonyl]-N-hydroxy-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxamide, 835-[(4-tert-butylphenyl)sulfonyl]-N-hydroxy-4,5,6,7-tetahydrothieno[3,2-c]pyridine-2-carboxamide,84N-hydroxy-6-[(5-methyl-1-phenyl-1H-pyrazol-4-yl)carbonyl]-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide, 85N-hydroxy-6-(propylsulfonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide,86N⁶-[2-fluoro-4-(trifluoromethyl)phenyl]-N²-hydroxy-4-methyl-4,7-dihydrothieno[2,3-c]pyridine-2,6(5H)-dicarboxamide, 876-[2-(4-chlorophenoxy)ethyl]-N-hydroxy-7-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide, 886-[(3-tert-butyl-1-methyl-1H-pyrazol-5-yl)carbonyl]-N-hydroxy-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide, 89N-hydroxy-6-({[3-(trifluoromethyl)phenyl]sulfanyl}acetyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide, 90N¹⁰-[4-chloro-3-(trifluoromethyl)phenyl]-N²-hydroxy-4,5,6,7,8,9-hexahydro-4,8-epiminocycloocta[b]thiophene-2,10-dicarboxamide, 91N-hydroxy-6-(quinolin-2-ylmethyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide,9210-[(1-cyclopropyl-1H-pyrrol-2-yl)carbonyl]-N-hydroxy-4,5,6,7,8,9-hexahydro-4,8-epiminocycloocta[b]thiophene-2-carboxamide, 93N-hydroxy-6-{[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl}acetyl]-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide, 94N-hydroxy-6-(3-methyl-2-furoyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide,95N-hydroxy-6-(quinolin-6-ylcarbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide,96N-hydroxy-5-({5-[3-(trifluoromethyl)phenyl]-3-thienyl}sulfonyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxamide, 975-[(4-tert-butylphenyl)sulfonyl]-N-hydroxy-7,7-dimethyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxamide, 98N-hydroxy-6-[(4-methyl-1,3-thiazol-5-yl)carbonyl]-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide, 99N-hydroxy-6-(quinolin-8-ylcarbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide,or 1006-[(4,6-dimethoxypyrimidin-2-yl)carbonyl]-N-hydroxy-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide.


17. The compound of claim 2, wherein the compound is: 101N-hydroxy-5-[5-(3-methyl-1-benzothien-2-yl)-1,3-thiazol-2-yl]-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxamide, 102N-hydroxy-6-({5-[3-(trifluoromethyl)phenyl]-3-thienyl}sulfonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide, 103N²-hydroxy-N⁶-(4-methylbenzyl)-4,7-dihydrothieno[2,3-c]pyridine-2,6(5H)-dicarboxamide,10410-[2-(4-chlorophenoxy)ethyl]-N-hydroxy-4,5,6,7,8,9-hexahydro-4,8-epiminocycloocta[b]thiophene-2-carboxamide, 106N6-[2-fluoro-5-(trifluoromethyl)phenyl]-N2-hydroxy-4,7-dihydrothieno[2,3-c]pyridine-2,6(5H)-dicarboxamide, 107N-hydroxy-6-[(5-methyl-3-phenylisoxazol-4-yl)carbonyl]-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide, 1086-[(3-chloro-1-methyl-1H-indol-2-yl)carbonyl]-N-hydroxy-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide, 109N2-hydroxy-N5-(4-methoxybenzyl)-6,7-dihydrothieno[3,2-c]pyridine-2,5(4H)-dicarboxamide,1106-[5-(3-chlorophenyl)-1,3-thiazol-2-yl]-N-hydroxy-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide, 111N-hydroxy-6-(4-methoxybenzyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide,1126-{[2-(4-tert-butylphenyl)-4-methyl-4H-furo[3,2-b]pyrrol-5-yl]carbonyl}-N-hydroxy-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide, 1135-[2-(benzylamino)pyrimidin-4-yl]-N-hydroxy-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxamide,1146-{[2-(4-chloro-2-methoxyphenyl)-4-methyl-4H-furo[3,2-b]pyrrol-5-yl]carbonyl}-N-hydroxy-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide, 1155-{[2-(5-cyano-2-thienyl)-4-methyl-4H-furo[3,2-b]pyrrol-5-yl]carbonyl}-N-hydroxy-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxamide, 116N-hydroxy-6-[(1-methyl-1H-pyrrol-2-yl)carbonyl]-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide, 117N6-[4-chloro-3-(trifluoromethyl)phenyl]-N2-hydroxy-4,7-dihydrothieno[2,3-c]pyridine-2,6(5H)-dicarboxamide, 1186-[(4-tert-butylphenyl)acetyl]-N-hydroxy-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide,119N-hydroxy-7,7-dimethyl-5-(quinolin-2-ylmethyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxamide, 120N-hydroxy-6-[(4′-methoxybiphenyl-4-yl)sulfonyl]-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide, 1216-[(4-tert-butylphenyl)sulfonyl]-7-(2-fluorophenyl)-N-hydroxy-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide, 1226-[3-(2,3-dihydro-1H-indol-1-yl)-3-oxopropyl]-N-hydroxy-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide, 1236-{[2-(5-cyano-2-thienyl)-4-methyl-4H-furo[3,2-b]pyrrol-5-yl]carbonyl}-N-hydroxy-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide, 1245-[(4′-fluorobiphenyl-3-yl)sulfonyl]-N-hydroxy-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxamide,1256-[(3,5-dimethyl-1H-pyrazol-1-yl)acetyl]-N-hydroxy-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide, 126N-hydroxy-5-{5-[4-(trifluoromethyl)phenyl]-1,3-thiazol-2-yl}-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxamide, 127N-hydroxy-6-[(1-phenyl-1H-pyrazol-4-yl)carbonyl]-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide, 1286-[(1-cyclopropyl-1H-pyrrol-2-yl)carbonyl]-7-(2-fluorophenyl)-N-hydroxy-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide, 129N-hydroxy-5-{[5-(2-methoxyphenyl)-1,2,4-oxadiazol-3-yl]methyl}-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxamide, 130N-hydroxy-6-{[5-(2-methoxyphenyl)-1,2,4-oxadiazol-3-yl]methyl}-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide, 1316-[3,5-bis(acetylamino)benzoyl]-N-hydroxy-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide,132N2-hydroxy-N6-(5-methyl-3-phenylisoxazol-4-yl)-4,7-dihydrothieno[2,3-c]pyridine-2,6(5H)-dicarboxamide, 133N-hydroxy-6-[3-(1H-pyrazol-1-yl)benzoyl]-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide,1346-[3-(2,3-dihydro-1H-indol-1-yl)-3-oxopropyl]-N-hydroxy-7-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide, 135N-hydroxy-5-(propylsulfonyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxamide,1366-[4-(benzylamino)pyrimidin-2-yl]-N-hydroxy-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide,137N6-[(1S)-1-(4-chlorophenyl)ethyl]-N2-hydroxy-4,7-dihydrothieno[2,3-c]pyridine-2,6(5H)-dicarboxamide, 138N-hydroxy-7-methyl-6-{5-[4-(trifluoromethyl)phenyl]-1,3-thiazol-2-yl}-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide, 139N2-hydroxy-N6-(4-isopropylphenyl)-4,7-dihydrothieno[2,3-c]pyridine-2,6(5H)-dicarboxamide,1406-(3,5-difluorobenzoyl)-N-hydroxy-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide,1425-{[2-(4-tert-butylphenyl)-4-methyl-4H-furo[3,2-b]pyrrol-5-yl]carbonyl}-N-hydroxy-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxamide, 1437-(2-fluorophenyl)-N-hydroxy-6-[3-(trifluoromethoxy)benzyl]1-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide, 144N-hydroxy-6-[5-(4-methoxyphenyl)-1,3-thiazol-2-yl]-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide, 145N-hydroxy-5-({4-methyl-2-[3-(trifluoromethyl)phenyl]-4H-furo[3,2-b]pyrrol-5-yl}carbonyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxamide, 146N-hydroxy-6-(1,3-thiazol-4-ylcarbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide,147N6-[(1R)-1-(4-chlorophenylethyl]-N2-hydroxy-4,7-dihydrothieno[2,3-c]pyridine-2,6(5H)-dicarboxamide, 1496-[(1-ethyl-3-methyl-1H-pyrazol-5-yl)carbonyl]-N-hydroxy-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide, or 1505-[2-(4-chlorophenoxy)ethyl]-N-hydroxy-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxamide.


18. The compound of claim 2, wherein the compound is: 151N-hydroxy-5-[(4′-methoxybiphenyl-4-yl)sulfonyl]-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxamide, 152N-hydroxy-6-[(4-methyl-2-phenylpyrimidin-5-yl)carbonyl]-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide, 153N-hydroxy-3-methyl-5-(propylsulfonyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxamide,154N⁵-[(1R)-1-(4-chlorophenypethyl]-N²-hydroxy-6,7-dihydrothieno[3,2-c]pyridine-2,5(4H)-dicarboxamide, 155N⁶-(4-chlorobenzyl)-N²-hydroxy-4,7-dihydrothieno[2,3-c]pyridine-2,6(5H)-dicarboxamide,156N-hydroxy-6-(2,3,5,6-tetrafluorobenzoyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide,1575-[4-(benzylamino)pyrimidin-2-yl]-N-hydroxy-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxamide,158N-hydroxy-6-[(5-methoxy-1-methyl-1H-indol-2-yl)carbonyl]-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide, 1596-[(5-amino-1H-pyrazol-4-yl)carbony]-N-hydroxy-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide, 1606-[(4-tert-butylphenyl)sulfonyl]-N-hydroxy-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide,162N-hydroxy-7,7-dimethyl-5-({4-methyl-2-[3-(trifluoromethyl)phenyl]-4H-furo[3,2-b]pyrrol-5-yl}carbonyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxamide, 163N2-hydroxy-N6-(4-iodophenyl)-4,7-dihydrothieno[2,3-c]pyridine-2,6(5H)-dicarboxamide,1646-[3-fluoro-5-(trifluoromethyl)benzoyl]-N-hydroxy-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide, 165N-hydroxy-5-[4-(trifluoromethyl)benzyl]-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxamide,166N-hydroxy-5-[(3-methoxy-1-methyl-1H-pyrrol-2-yl)carbonyl]-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxamide, 167N-hydroxy-6-[5-(3-methyl-1-benzothien-2-yl)-1,3-thiazol-2-yl]-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide, 1685-[(3-chloro-1-methyl-1H-indol-2-yl)carbonyl]-N-hydroxy-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxamide, 169N6-(4-butylphenyl)-N2-hydroxy-4,7-dihydrothieno[2,3-c]pyridine-2,6(5H)-dicarboxamide,171N-hydroxy-6-[4-(trifluoromethyl)benzoyl]-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide,173 tert-butyl2-[(hydroxyamino)carbonyl]-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-carboxylate,174N-hydroxy-6-[(3-methoxy-1-methyl-1H-pyrrol-2-yl)carbonyl]-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide, 175N-hydroxy-6-[(5-methoxy-1-methyl-1H-indol-2-yl)carbonyl]-4-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide, 176N2-hydroxy-N6-mesityl-4,7-dihydrothieno[2,3-c]pyridine-2,6(5H)-dicarboxamide,1776-[(3,5-dimethylisoxazol-4-yl)carbonyl]-N-hydroxy-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide, 1786-(2,5-dimethyl-3-furoyl)-N-hydroxy-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide,179N-hydroxy-6-(quinolin-2-ylcarbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide,180N-hydroxy-6-({4-methyl-2-[3-(trifluoromethyl)phenyl]-4H-furo[3,2-b]pyrrol-5-yl}carbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide, 181N-hydroxy-6-[4-(trifluoromethyl)benzyl]-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide,1826-(4-fluorobenzoyl)-N-hydroxy-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide,1836-[(4,5-dichloro-1-methyl-1H-pyrrol-2-yl)carbonyl]-N-hydroxy-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide, 1846-{[3-(4-fluorophenyl)-5-methylisoxazol-4-yl]carbonyl}-N-hydroxy-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide, 185N-hydroxy-6-{[4-(trifluoromethyl)phenyl]acetyl}-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide, 1866-[(3-ethyl-1-methyl-1H-pyrazol-5-yl)carbonyl]-N-hydroxy-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide, 187N-hydroxy-6-[(5-methyl-1-phenyl-1H-pyrazol-4-yl)carbonyl]-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide, 1886-[(4-tert-butylphenyl)acetyl]-N-hydroxy-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide,189N5-(2,6-difluorophenyl)-N2-hydroxy-7,7-dimethyl-6,7-dihydrothieno[3,2-c]pyridine-2,5(4H)-dicarboxamide, 1905-(4-tert-butylbenzoyl)-N-hydroxy-7,7-dimethyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxamide,191N5-benzyl-N2-hydroxy-7,7-dimethyl-6,7-dihydrothieno[3,2-c]pyridine-2,5(4H)-dicarboxamide,1925-[(3-chloro-1-benzothien-2-yl)carbonyl]-N-hydroxy-7,7-dimethyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxamide, 1935-(4-chlorobenzoyl)-N-hydroxy-3-methyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxamide,194N-hydroxy-3-methyl-5-[(1-methyl-1H-pyrrol-2-yl)carbonyl]-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxamide, 1955-(1-benzothien-2-ylcarbonyl)-N-hydroxy-7,7-dimethyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxamide, 196N5-(4-cyanophenyl)-N2-hydroxy-7,7-dimethyl-6,7-dihydrothieno[3,2-c]pyridine-2,5(4H)-dicarboxamide, 197N-hydroxy-3-methyl-5-[(2-methyl-1,3-thiazol-4-yl)carbonyl]-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxamide, 1985-(3,4-dihydro-2H-1,5-benzodioxepin-7-ylcarbonyl)-N-hydroxy-7,7-dimethyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxamide, 199N-hydroxy-3-methyl-5-[(4-methyl-2-pyridin-2-yl-1,3-thiazol-5-yl)carbonyl]-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxamide, or 200N5-(3,4-dimethylphenyl)-N2-hydroxy-7,7-dimethyl-6,7-dihydrothieno[3,2-c]pyridine-2,5(4H)-dicarboxamide.


19. The compound of claim 2, wherein the compound is: 201N²-hydroxy-7,7-dimethyl-N5-[(1S)-1-phenylethyl]-6,7-dihydrothieno[3,2-c]pyridine-2,5(4H)-dicarboxamide, 202N²-hydroxy-7,7-dimethyl-N5-[(1S)-1-phenylethyl]-6,7-dihydrothieno[3,2-c]pyridine-2,5(4H)-dicarboxamide, 2035-[(3S,5S,7S)-1-adamantylcarbonyl]-N-hydroxy-3-methyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxamide, 2045-(2,2-dimethylpropanoyl)-N-hydroxy-3-methyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxamide,2055-(1-benzothien-2-ylcarbonyl)-N-hydroxy-3-methyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxamide, 206N⁵-(2,3-dihydro-1-benzofuran-5-yl)-N²-hydroxy-7,7-dimethyl-6,7-dihydrothieno[3,2-c]pyridine-2,5(4H)-dicarboxamide, 2075-(biphenyl-4-ylcarbonyl)-N-hydroxy-7,7-dimethyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxamide, 208N-hydroxy-7,7-dimethyl-5-[(3-phenyl-1H-indol-2-yl)carbonyl]-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxamide, 209N-hydroxy-5-(4-methoxybenzoyl)-3-methyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxamide,210N-hydroxy-7,7-dimethyl-5-[(1-methyl-1H-pyrrol-2-yl)carbonyl]-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxamide, 211N-hydroxy-7,7-dimethyl-5-[(5-pyridin-2-yl-2-thienyl)carbonyl]-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxamide, 212 tert-butyl2-[(hydroxyamino)carbonyl]-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-carboxylate,213N²-hydroxy-7,7-dimethyl-N⁵-(2-phenylethyl)-6,7-dihydrothieno[3,2-c]pyridine-2,5(4H)-dicarboxamide,214N-hydroxy-5-(4-methoxybenzoyl)-7,7-dimethyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxamide,2155-(1-benzofuran-2-ylcarbonyl)-N-hydroxy-7,7-dimethyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxamide, 2165-(1-benzofuran-2-ylcarbonyl)-N-hydroxy-3-methyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxamide, 217N-hydroxy-3-methyl-5-(pyridin-2-ylcarbonyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxamide,2185-(4-chlorobenzoyl)-N-hydroxy-7,7-dimethyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxamide,219N-hydroxy-3-methyl-5-(phenylacetyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxamide,220N-hydroxy-7,7-dimethyl-5-(pyridin-2-ylcarbonyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxamide, 2215-[(3-chloro-1-benzothien-2-yl)carbonyl]-N-hydroxy-3-methyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxamide, 222N-hydroxy-7,7-dimethyl-5-[(2-methyl-1,3-thiazol-4-yl)carbonyl]-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxamide, 224N-hydroxy-7,7-dimethyl-5-[(1-methylcyclohexyl)carbonyl]-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxamide, 2255-(4-tert-butylbenzoyl)-N-hydroxy-3-methyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxamide,226N-hydroxy-7,7-dimethyl-5-(2-thienylcarbonyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxamide,227N-hydroxy-7,7-dimethyl-5-(phenylacetyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxamide,228N-hydroxy-7,7-dimethyl-5-[(4-methyl-2-pyridin-2-yl-1,3-thiazol-5-yl)carbonyl]-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxamide, 2295-butyryl-N-hydroxy-3-methyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxamide,232N-hydroxy-3-methyl-5-[(1-methylcyclohexyl)carbonyl]-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxamide, 2335-(biphenyl-4-ylcarbonyl)-N-hydroxy-3-methyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxamide,2345-(2-chlorobenzoyl)-N-hydroxy-7,7-dimethyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxamide,235N-hydroxy-6-(pyridin-3-ylmethyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide,236N5-[2-(dimethylamino)ethyl]-N2-hydroxy-7,7-dimethyl-6,7-dihydrothieno[3,2-c]pyridine-2,5(4H)-dicarboxamide, 237N-hydroxy-3-methyl-5-[(4-methylpiperidin-4-yl)carbonyl]-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxamide, 238N-hydroxy-6-(piperidin-4-ylcarbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide,239N-hydroxy-5-[(2S)-3-methyl-2-(methylamino)butanoyl]-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxamide, or 2405-(4-chlorobenzoyl)-N-hydroxy-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxamide.